Recent Advances in Pancreatic Cancer: Biology, Treatment, and Prevention Divya Singh, Ghanshyam Upadhyay, Rakesh K. Srivastava, Sharmila Shankar PII: DOI: Reference:
S0304-419X(15)00035-9 doi: 10.1016/j.bbcan.2015.04.003 BBACAN 88039
To appear in:
BBA - Reviews on Cancer
Received date: Revised date: Accepted date:
30 January 2015 28 April 2015 30 April 2015
Please cite this article as: Divya Singh, Ghanshyam Upadhyay, Rakesh K. Srivastava, Sharmila Shankar, Recent Advances in Pancreatic Cancer: Biology, Treatment, and Prevention, BBA - Reviews on Cancer (2015), doi: 10.1016/j.bbcan.2015.04.003
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Recent Advances in Pancreatic Cancer: Biology, Treatment, and Prevention
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Divya Singh1, Ghanshyam Upadhyay1*, Rakesh K. Srivastava2*, Sharmila Shankar2,3*
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Department of Biology, City College of New York, 160 Convent Avenue, New York, NY-10031 Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128.
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Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108.
Email:
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[email protected] [email protected]
[email protected] [email protected]
*Corresponding author: Dr. Rakesh Srivastava ([email protected]) Dr. Sharmila Shankar ([email protected])
ACCEPTED MANUSCRIPT Abstract Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in United
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States. Efforts have been made towards the development of the viable solution for its
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treatment with constrained accomplishment because of its complex biology. It is well
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established that pancreatic cancer stem cells (CSCs), albeit present in a little count, contribute incredibly to PC initiation, progression, and metastasis. Customary chemo and
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radiotherapeutic alternatives, however, expands general survival, the related side effects
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are the significant concern. Amid the most recent decade, our insight about molecular and cellular pathways involved in PC and role of CSCs in its progression has increased
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enormously. Presently the focus is to target CSCs. The herbal products have got much
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consideration recently as they, usually, sensitize CSCs to chemotherapy and target molecular signaling involved in various tumors including PC. Some planned studies have
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indicated promising results proposing that examinations in this course have a lot to offer for the treatment of PC. Although preclinical studies uncovered the importance of herbal products in attenuating pancreatic carcinoma, limited studies have been conducted to evaluate their role in clinics. The present review provides a new insight to recent advances in pancreatic cancer biology, treatment and current status of herbal products in its anticipation.
ACCEPTED MANUSCRIPT Abbreviations: Oct4: octamer-binding transcription factor 4; ABCG2: ATP-binding cassette sub-family
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G member 2; CXCR4; C-X-C chemokine receptor type 4; FGF: fibroblast growth factor;
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Frizzled-9: frizzled class receptor 9; Glut1: glucose transporter 1; Foxa2: forkhead box
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A2; Sox2: sex determining region Y box 2; Klf4: kruppel like factor 4; c-Myc: v-Myc avian myelocytomatosis viral oncogene homolog; FGF; fibroblast growth factor; ESA:
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epithelial-specific antigen; ALDH1: acetaldehyde dehydrogenases 1; ABCB1: ATP-
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binding cassette sub-family B member 1; MDR1: multidrug resistance protein 1; DCLK1: doublecortin-like kinase 1; Cdkn2a: cyclin-dependent kinase inhibitor 2a; Dpc4
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or Smad4: deleted in pancreatic carcinoma, locus 4; STAT3: signal transducer and
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activator of transcription 3; TNF-α: tumor necrosis factor α; MCP-1: monocyte chemotactic protein-1; EGF: epidermal growth factor; EGFR: epidermal growth factor
factor;
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receptor; PDGF: platelet-derived growth factor; G-CSF: granulocyte colony-stimulating GM-CSF:
granulocyte-macrophage
colony-stimulating
factor;
TGF-β
:
transforming growth factor beta; Chk2: checkpoint kinase 2; COX-2: cyclooxygenase-2; IGF-1R: insulin-like growth factor-1 receptor; VEGF: vascular endothelial growth factor; HIF1α: hypoxia inducible factor 1α; MMP: matrix metalloproteinase, TWIST1: Twistrelated protein 1; ICAM1: intercellular adhesion molecule 1; Bcl-2: B-cell lymphoma 2, Bcl-xL: B-cell lymphoma extra-large, Bad: Bcl-2-associated death promoter; Bak: Bcl-2 homologous antagonist/killer; Bax: Bcl-2-associated X protein; Mcl-1: induced myeloid leukemia cell differentiation protein; Pdx1: pancreatic and duodenal homeobox 1, uPA: urokinase-type plasminogen activator; uPAR: urokinase-type plasminogen activator receptor; MAPK: mitogen activated protein kinase; FoxO1: forkhead box O1; FoxO3:
ACCEPTED MANUSCRIPT forkhead box O3; PI3K: phosphatidylinositol 3-kinase; PARP: peroxisome proliferatoractivated receptor; PTEN: phosphatase and tensin homolog; PDGFRα: alpha-type
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platelet-derived growth factor receptor; IGF2R: insulin-like growth factor 2 receptor;
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ENG: endoglin, ALK1: activin receptor-like kinase 1; FKHRL1: forkhead box O3a; FKHR: forkhead box O1: AFX: forkhead box O4; TP53: tumor protein p53; TRAIL:
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tumor necrosis factor-related apoptosis-inducing ligand; Cdk4: cyclin-dependent kinase
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4; Raf-1: RAF proto-oncogene serine/threonine-protein kinase; Her-2: human epidermal growth factor receptor 2; EMT: endothelial to meseanchymal transition; DR: death
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receptor; EpCAM: epithelial cell adhesion molecule; vWF: von Willebrand factor; PCNA: proliferating cell nuclear antigen; Hsp: heat shock potein; XIAP: X-linked apoptosis
protein;
IAP:
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of
inhibitor
of
apoptosis
protein;
Pdk1:
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inhibitor
phosphoinositide-dependent kinase-1; mTOR: mammalian target of rapamycin; ERK:
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extracellular-signal-regulated kinases; JNK: c-Jun N-terminal kinases; HDAC: histone deacetylases; p38: P38 mitogen-activated protein kinases; ROS: reactive oxygen species
ACCEPTED MANUSCRIPT Introduction The burden of pancreatic cancer (PC) has continuously increased worldwide. It is a
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serious health concern and fourth leading cause of cancer-related death in United States
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of America [1, 2]. PC is described as a type of gastrointestinal tumor with a poor
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anticipation and a high level of danger and death rate [3]. More than 90% of pancreatic tumors have inception from the ductal epithelium of pancreas consequently termed as
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pancreatic ductal adenocarcinoma (PDAC). It is disturbing to see that frequency rate of
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the pancreatic tumor is relentlessly expanding in the western world [4]. The danger components for pancreatic growth incorporate smoking, obesity and high utilization of
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processed meat. Age is positively correlated with pancreatic cancer incidences, and the
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larger part of cases are diagnosed over the age of 60 [5]. The introductory indications of patients with PDAC are back agony and dyspepsia with additional disturbing
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manifestations like the new onset of diabetes, jaundice, and unconstrained profound vein thrombosis and weight reduction. When one begins perceiving, the tumor typically, spreads to the encompassing tissues or distant organs. For the tumors spotted in the head region of pancreas, the determination is actually productive and they are diagnosed relatively early because of biliary impediment. Nonetheless, the tumors in the body and tail of pancreas regularly stay asymptomatic until late in disease stage. Most of the patients (~80%) are identified with unresectable locally advanced or metastatic disease and the major cause is the delayed diagnosis and lack of specific blood or urine biomarkers to identify patients with increased risk of developing pancreatic cancer [6-9]. The routine diagnostics incorporate transabdominal ultrasound in the introductory
ACCEPTED MANUSCRIPT assessment of the jaundiced patient alongside computed tomography (CT) scan or magnetic resonance imaging (MRI).
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Despite the fact that the survival rate for most diseases has been increased lately in a
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couple of decades, little change is seen in the case of pancreatic cancer. The usual
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survival rate for pancreatic disease patients is under six months, and just 3% patients survive over 5-years [6-9]. The reason is attributed to various factors including silent
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nature in early stages, aggressive tumor biology, the low scope of surgical management,
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and lack of effective systemic therapies. Although, the current procedures including surgery, chemotherapy, radiation, and immunosuppressants, have made great advances in
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diminishing tumor frequencies and death rates, pancreatic cancer remains a continuing
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challenge to the researchers and treatment strategies at present utilized are not very encouraging [10]. There are exceptionally poor post-surgery survival rates even when the
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pancreatic tumor is surgically resected. Safety concerns related with these medications/techniques are likewise a significant issue for their accomplishment in the treatment of the disease [6-9]. The prevalent chemotherapeutic choices for the cancer treatment prolong the life of pancreatic cancer patients minimally, and the survival span in a large portion of the cases is not over one year. Since limited treatment choices are accessible, and it additionally shows resistance against chemo- and radiotherapies, it is important to find novel and viable methodologies for the treatment of pancreatic cancer [10]. Although the potential use of herbal components for the protection against various cancers began several decades ago, studies to understand the mechanism of their action at biochemical, genomic, and proteomic levels started very recently. Many plant products
ACCEPTED MANUSCRIPT that are rich sources of phytochemicals, such as triterpenes, flavonoids or polyphenols, are now established potent chemopreventive agents [11-15]. The phenolic substances are
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isolated from the wide range of vascular plants and have the ability to reduce and
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scavenge free radicals [16, 17]. Epidemiological studies have shown the reduced risk of pancreatic cancer by increased consumption of fruits and vegetables [18]. In the recent
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past, a number of preclinical studies have demonstrated various degrees of the efficacy of
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herbal products both in vitro and in vivo [18]. Certain dietary agents, for example, resveratrol and curcumin, have been demonstrated to potentiate the standard
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chemotherapy [18]. It has been observed that herbal products target different pathways simultaneously therefore any solution including these products may be a smart thought
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for better results. Many groups are working in this direction, and the outcomes are promising towards the improvement of new helpful cure. In this review, we will examine
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the biology of the pancreatic tumor, diagnosis, treatment techniques and clinical trials. We will likewise concentrate on the plausible role of herbal products, alone or in combination with systemic chemopreventive medications, in the treatment of the pancreatic tumor.
Biology of Pancreatic Cancer The biology of pancreatic cancer is perplexing and inadequately caught on. Pancreas has both exocrine and endocrine cells that can structure tumors; however, the likelihood is more for exocrine cells. The vast majority of the exocrine tumors are adenocarcinomas that begin in organ cells in the ductal epithelium and advances from premalignant injuries to the entirely invasive tumor. Tumors of the endocrine pancreas, commonly termed as islet cell tumors or neuroendocrine tumors, are less common and can be characterized
ACCEPTED MANUSCRIPT into gastrinomas, insulinomas, glucagonomas, somatostatinomas, VIPomas, PPomas and so forth.
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The microenvironment of the pancreatic tumor is made out of a few components, for
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example, pancreatic cancer bulk cells, pancreatic cancer stem cells (pancreatic CSCs),
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and the thick, ineffectively vascularized stroma. The studies suggest that the stroma likewise regulate the pancreatic tumor growth and development, intrusion and metastasis
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separated from its movement as the mechanical boundary. These stromal cells
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consistently interface with cancer cells by different autocrine and paracrine secretion of the pancreas, for example, platelet-derived growth factor (PDGF), transforming growth
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factor β (TGF-β) and cytokines [19]. These development variables fortify a critical
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segment of stroma called pancreatic stellate cells, which in turn express α–smoothmuscle actin and produce rich collagen fibers. These fibers add to tumor hypoxia (a
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primary stimulator of tumor movement and metastasis by influencing angiogenesis), cell survival, and apoptotic pathways [19]. Hypoxia is likewise proposed to be a major cause for drug/therapy resistance in different tumors [20, 21]. Pancreatic tumor cells apparently grow around a population of cancer stem cells (CSCs) that have the capability of self-renewal and multi-lineage differentiation [22] (Fig 1). Pancreatic CSCs can be isolated by flow cytometry utilizing CD44, CD24, and ESA as surface markers [23]. Although CD44+/CD24+/ESA+ cells constitute only 0.2-0.8% of the total cell population, they are capable of forming tumor spheres [24]. Other markers for pancreatic CSCs are CD133, CXCR4, c-Met and ALDH1 [25-28]. CXCR4 assumes an essential part in the tumor invasion and metastasis and the cells positive for both CD133 and CXCR4, show higher metastatic potential than other populations [26, 29]. In
ACCEPTED MANUSCRIPT a recent study, it has been demonstrated that human PDACs contain CSCs with high levels of CXCR4 and ABCB1, and such patients had reduced survival rate [30]. Recently
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Shankar et al. effectively demonstrated the tumorigenic potential of pancreatic CSCs
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isolated from human pancreatic tumors in NOD/SCID mice utilizing surface markers CD44, ESA, CD133, and CD24 [10]. These cells were highly tumorigenic and were
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likewise expressing ALDH and pluripotency maintaining factor, Oct-4 [10]. They further
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indicated high expression of CD133, CD24, CD44, ESA, Nanog, Notch1, MDR1 and ABCG2 in these CSCs (CD133+CD44+CD24+ESA+ cell population) contrasted with
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CD133−CD44−CD24−ESA− cell population [10].
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Various elements regulate the properties and conduct of pancreatic CSCs, for example,
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nestin can balance attack or metastasis of pancreatic CSCs, Oct-4 and Nanog can direct pancreatic CSC’s conduct and metastasis to different organs, DCLK1 can segregate
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between normal and tumoral stem cells and Sox2 controls cell proliferation and differentiation [31]. Furthermore, c-Kit and Kras likewise tweak the movement of pancreatic adenocarcinoma [32]. Epithelial to mesenchymal transition (EMT), a process of change of epithelial attributes into mesenchymal properties, is an urgent process for tumor progression and is proposed to be in charge for the appearance of cells with stem cell-like properties [33]. CSCs are thought to be the major contributory element to the absence of effective treatment for pancreatic malignancy and are in charge of tumorigenesis, metastasis, and development of chemo and radioresistance [24]. A recent study exhibited that PANC-1 cancer cell line, steadily overexpressing Oct4 and Nanog, show chemoresistance, multiplication, relocation, intrusion, and tumorigenesis in vitro and in vivo [34].
ACCEPTED MANUSCRIPT Moreover, the ALDH+CD44+CD24+ cell population is well reported to be impervious to treatment with gemcitabine [35]. Removal of CSCs is essential for robust tumor
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be a superior alternative for pancreatic cancer prevention.
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treatment, as CSCs stay untouched. Hence, drugs that can specifically target CSCs could
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Pancreatic cancer is hereditarily complex and heterogeneous in nature. Different malady conditions, for example, pancreatitis, cystic fibrosis, and inflammation have their effect
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on the initiation of pancreatic cancer and its malignant progression [36, 37]. Mutations in
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four critical genes namely Kras2, Cdkn2a, TP53 and Dpc4 (or Smad4) are frequently seen in pancreatic malignancy patients. The vast majority of the cancer patients carry one
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or more of these mutations [38]. The observed frequency of Kras mutation is more than
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90%, however, the rate of inactivation mutation of Cdkn2a, TP53, and Dpc4 are 95%, 75% and 50% respectively [39, 40]. The mutation in Kras2 brings about the consistent
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expression of irregular Ras protein that causes aberrant activation of cell proliferation and survival pathways [19]. With increasing age, the likelihood of acquiring activating mutations in Kras2 gene increases in the major organs such as lung, pancreas, colon, and other tissues. On the other hand Cdkn2a, TP53 and Dpc4 are the tumor suppressors and mutations in these genes result in their inactivation, which facilitate the proliferation and survival signaling [19, 41]. Moreover, a recent study called attention to the loss of function mutation in SWI/SNF nucleosome remodeling complex in 23% pancreatic adenocarcinomas [42]. Signaling Pathways in Pancreatic Cancer
ACCEPTED MANUSCRIPT Genetic mutations serve as the basis for abbrent signaling pathways. A comprehensive study with more than 24 pancreatic cancer cases, an average of 63 relevent genetic
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abnormalities (mainly point mutations) per tumor were classified as likely to be relevent
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in its pathogenesis [43] (reviewed in [19]). These mutations can be clubbed in 12 noteworthy signaling pathways including STAT3, Smad/TGF-β, Wnt, Notch, PI3K/Akt,
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sonic hedgehog and so forth [43] (reviewed in [19]). Aberrant signaling in these cellular
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events has been implicated in the development and progression of pancreatic tumors by
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permitting increased proliferation, angiogenesis, survival, and metastasis (Fig 2). STAT3 Pathway
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Signal transducer and activator of transcription 3 (STAT3), encoded by STAT3 gene, is
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activated in a wide variety of signaling pathways. It mediates diverse responses,
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including transmission of the signals of cytokines and growth factors from the cell membrane to the nucleus to regulate gene expression for cell development, differentiation, proliferation, survival, and angiogenesis [44-46] (Fig 3). A range of cytokines including interleukin (IL)-6, IL-9, IL-10, IL-27, tumor necrosis factor α (TNFα), and monocyte chemotactic protein-1 (MCP-1) activate the STAT3 pathway [47-49]. Various growth factors, for example, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), granulocyte colony-stimulating factor (G-CSF), and granulocytemacrophage colony-stimulating factor (GM-CSF) also activate this pathway [44-49]. Primary functions of activated STAT3 pathway incorporate cell proliferation by upregulating cyclin D1 and cyclin B1 and inhibition of apoptosis by up-regulating Bcl-2, Bcl-xL, Mcl-1. Initiated STAT3 assumes a discriminating part in tumorigenesis by
ACCEPTED MANUSCRIPT controlling angiogenesis (VEGF, FGF, and HIF1α), invasion and metastasis (MMP2, MMP9, TWIST, and ICAM1) [44-49].
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STAT3 activation has been detected in diverse type of malignancies, and its inhibition by
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use of inhibitors or short interfering RNA has prompted to reverse the malignant
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phenotype. STAT3 activation has been portrayed in almost 70% of solid and hematological malignancies [50]. Studies in conditional knockout mice have
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demonstrated that STAT3 pathway is latent in typical pancreas and is not needed for any
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vital process related to pancreatic development and homeostasis [51]. Nevertheless, it is constitutively activated in PDAC by phosphorylation of Tyr705 in human tumor
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specimens and also in various PDAC cell lines [52-55]. Further, STAT3 is necessary for
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the development of ADM process (acinar-to-ductal metaplasia), which is an early event in PDAC pathogenesis mediated by ectopic expression of the Pdx1 [54]. It is remarkable
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that Pdx1 is a transcription factior and a key regulator of early pancreatic development [54]. Another study showed that with malignant transformation, activated STAT3 promotes proliferation of cells by regulating G1/S-phase progression and supports the malignant phenotype of human pancreatic cancer [52]. IL-6 signaling dependent activation of STAT3 plays an important role in promoting PanIN progression and the PDAC development, in addition to oncogenic KrasG12D transformation [56]. The myeloid cells in the pancreas induce STAT3 activation by releasing IL-6, which promote PanIN progression and the PDAC development. Smad/TGF-β Pathway
ACCEPTED MANUSCRIPT The transforming growth factor beta (TGF-β) signaling pathway regulates various cellular processes like cell growth, cell differentiation, apoptosis and cellular homeostasis
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in both the adult organism and the developing embryo [57]. TGF-β signaling occurs from
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the membrane to the nucleus via Smad proteins [58]. Smads can be classified into 3 major groups; receptor-regulated Smads (R-Smad; Smad1, Smad2, Smad3, Smad5 and
[58]. Cascade is triggered by the binding of TGF-β
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(I-Smad; Smad6 and Smad7)
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Smad8/9), common-mediator Smad (co-Smad; Smad4) and agonistic or inhibitory Smads
superfamily ligand to a type II receptor which catalyzes the recruitment and
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phosphorylation of a type I receptor. Subsequently R-Smads are phosphorylated, linked with the coSmad and other factors, and finally accumulated in the nucleus to regulate the
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target gene expression. TGF-β receptor activation results in Smad2 and Smad3 phosphorylation, which then form heteromeric complexes with Smad4. Furthermore,
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Smad6 and Smad7, can prevent TGF-β signaling by interacting either with the receptor or with Smad2 and Smad3 [58].
TGF-β signaling pathway impairment because of inactivated Smad4 (DPC4) is often recognized in pancreatic carcinomas [59, 60]. Jonson et al., investigated a series of pancreatic carcinoma cell lines with respect to alterations of five Smad genes involved in TGF-β signaling, and demonstrated the structural rearrangement of Smad4 in 42% of these tumor cells [59]. Since, this pathway could likewise be influenced by other factors that regulate the activation of TGF-β
and its receptor genes, they further assessed
expression of uPA, uPAR, IGF2R, TGF-βR1-3, ENG, ALK1, TGF-β1-3, mutations of TGF-βR1-2, cell surface localization of TGF-βR2 and ENG, and TGF-β1 response in 14 pancreatic carcinoma cell lines [59]. The study suggested ALK5- Smad4 as a major
ACCEPTED MANUSCRIPT target for inactivation in pancreatic carcinomas and that the expression of TGF-βR2, TGF-βR3, and receptors involved in TGF-β activation are maintained [59].
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Wnt Pathway
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Wnt signaling pathway is a complex process and plays an important role in tumor
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development apart from its involvement in other physiological and pathological processes
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[61]. In canonical pathway, the ligand binding to its receptor (Frizzled/LRP receptor complexes) triggers a cascade of events that prevents β-catenin degradation inside the
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cytoplasm and permits its stabilization and translocation in nucleus where it binds to transcriptional factors of the Tcf/Lef family forming an activator complex. Abnormal
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Wnt/β-catenin signaling is reported in pancreatic cancer [62]. Activated Wnt signal leads
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to the accumulation of β-catenin in the nucleus where it activates specific target genes
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[63]. The accumulation of β-catenin is observed both in nucleus and cytoplasm in pancreatic cancer [61, 64-66]. The functional evidences are also accumulating that implicate a supporting role for β-catenin in PDAC maintenance and progression [61]. It has been also found that β-catenin accumulation and signaling could be increased through paracrine signaling taking place in the PDAC micro-environment [61]. In a recent investigation, it has been found that Wnt/β-catenin signaling inhibition by wnt-c59 results in reversal of TSA sensitivity, migration ability, and the EMT phenotype in trichostatin A-resistant Panc-1 cells (Panc-1/TSA) [67]. In spite of the fact that our understanding of the role of this pathway has increased during the last decade, the general mechanism by which β-catenin accumulation occurs in PDAC is poorly understood and needs further elucidation.
ACCEPTED MANUSCRIPT Notch Pathway Notch signaling is shown to regulate proliferation and apoptosis events in various cell
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types. The alterations in Notch signaling have various consequences including
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tumorigenesis [68, 69]. In mammals, four Notch receptors (Notch1-4) and five ligands
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(Jagged1, Jagged2, Delta-like 1(Dll-1), Dll-3, and Dll-4) have been accounted for to date [68, 70]. Binding of Notch ligand to an adjacent Notch receptor activates Notch signaling
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prompting the cleavage of Notch through a cascade of proteolytic cleavages by the
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metalloprotease, tumor necrosis factor-α-converting enzyme (TACE) and γ-secretase complexes [68, 71]. The cleavage by TACE generates Notch extracellular truncation
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(NEXT) which is subsequently cleaved by the γ-secretase complex releasing the active
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fragment Notch intracellular domain (NICD) from the plasma membrane. NICD translocates into the nucleus where it binds to members of the CSL transcription factor
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family and activates Notch target genes [68, 72]. Impaired Notch signaling is well reported in pancreatic cancers. Recently, it has been reported that inhibition of Notch signaling pathway by Notch1 siRNA or gammasecretase inhibitors, such as, MRK-003, MK-0752 etc., enhances chemosensitivity to gemcitabine in pancreatic cancer cells through activating apoptosis activity [73]. Abel et al. reported the significance of Notch pathway in maintaining cancer stem cell population in pancreatic cancer and investigated the connection of Notch pathway and percentage of the CSCs population. The inhibition of this pathway resulted in a reduced percentage of CSCs and tumor sphere formation; notwithstanding, activation demonstrated the inverse impact [74]. Further, Lee et al. suggested that the activation of the Notch pathway and the increase in CSCs might contribute to the failure of treatment in pancreatic cancer [75].
ACCEPTED MANUSCRIPT Notch has also been shown to be associated with the EMT in pancreatic cancer [72, 76]. It is remarkable that during the EMT process, epithelial cells gain the mesenchymal over
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endothelial characteristic thereby increasing in migratory and invasive capacity, leading
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to invasion and metastasis [77, 78].
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PI3K/Akt Pathway
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PI3K pathway acts via phosphorylation of FoxO proteins via Akt, which in turn impairs the DNA-binding ability and increases its affinity for 14-3-3 proteins [79]. These
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complexes are exported from the nucleus to cytoplasm leading to the inhibition of FoxOmediated survival pathways. Some other downstream effectors that regulate cell cycle
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arrest and apoptosis, such as, active FKHRL1, FKHR, and AFX are also translocated to
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the cytoplasm by similar mechanism [79]. Downstream effectors of the PI3K-Akt
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pathway are actively involved in a variety of vital and specialized functions such as differentiation and proliferation in diversified cells including adipocytes, hepatocytes, myoblasts, thymocytes and cancer cells [79]. PI3K/Akt pathway is activated in a variety of cells including fibroblastic, epithelial, and neuronal cells as survival signal. An elevated level of Akt has been reported in many types of tumors. Studies have shown the requirement of activated PI3K-Akt/FoxO signaling for the growth and survival of the pancreatic tumor. It has been found that the cells with elevated Akt levels are less sensitive to apoptosis stimuli. Akt regulates apoptosis directly by regulating its primary targets, Bad, and Caspase 9 and indirectly by controlling human telomerase reverse transcriptase subunit, FoxOs and IkappaB kinases and so forth [79].
ACCEPTED MANUSCRIPT Sonic Hedgehog Pathway Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted signaling
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proteins. Shh signaling is triggered by binding of the secreted Shh peptide to Patched
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(Ptch), which leads to inhibition of Ptch activity. Consequently, Smoothened (Smo) gets
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phosphorylated resulting in the activation of the Gli family of zinc-finger transcription factors and therefore target gene expression [80]. Shh signaling has diverse functions
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during vertebrate development and post-embryonically in tissue homeostasis [81, 82].
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Alteration in this pathway have been linked to various tumor types including pancreatic cancer [81, 82]. Activation of Shh signaling pathway has been reported to be involved in
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the regulation of the pancreatic CSC's expansion, whereas its inhibition (by impairing Gli
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binding to its promoters) has been demonstrated to upregulate DRs and Fas expression, curb Bcl-2 and PDGFRα expressions, and encourage apoptotic cell death in pancreatic
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CSCs [24]. Further, its inhibition has been shown to reduce tumor-associated stromal tissues, enhance gemcitabine uptake in tumor cells and prolong the average survival rate in pancreatic cancer mouse model [83]. Recently, Rodova et al. showed that inhibition of Shh pathway components, Gli transcriptional activity and its downstream targets by sulforaphane inhibited human pancreatic CSCs derived spheres and induced apoptosis by inhibition of Bcl-2 and activation of caspases in vitro [84]. Further, Li et al. showed that inhibition of Shh pathway by sulforaphane results in a marked reduction in EMT, metastatic, angiogenic markers with significant inhibition of tumor growth in mice. Since aberrant Shh signaling is frequently observed in pancreatic cancers, therapeutics that target Shh pathway and therefore CSCs, may improve the outcomes of patients with this devastating disease [85].
ACCEPTED MANUSCRIPT Treatment of Pancreatic Cancer: Chemotherapy and Radiotherapy The essential choice for pancreatic cancer treatment is its surgical removal. However, in
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advance metastatic stages, the treatment mainly aims to increase the survival by optimal
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control of metastases. Systemic chemotherapy may be utilized at any phase of pancreatic
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malignancy with the objective to minimize the patient’s disease-related symptoms and to prolong survival. Presently, a limited number of drugs are accessible for the treatment of
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the pancreatic tumor. Gemcitabine has been the reference regimen since 1997 when it
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was indicated better than 5-Fluorouracil (5-FU) in a phase III clinical trial [86]. A significant concern with 5-FU was the associated toxicity with its treatment, in particular,
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gastrointestinal toxicity. A combination of 5-FU and Fluoropyrimidine (S-1) could
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likewise be a decent choice as S-1 potentiates the antitumor activity of 5-FU and decreases gastrointestinal toxicity in pancreatic tumor mouse models [87]. In recent years
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different combinations, for example, the systemic treatment with Abraxane and Gemcitabine and the multidrug mix, FOLFIRINOX, have been attempted [88-109]. Despite the fact that FOLFIRINOX has been promising, it can have a remarkable reaction profile, constraining its utility in patients with poor baseline performance status [110]. Radiation therapy, combined with chemotherapy, may be used in patients whose cancers have grown beyond the pancreas and cannot be removed by surgery. Uses of radiation treatment alongside high-energy x-beams to kill cancer cells is extremely regular for the treatment of advanced stages of tumors. Pancreatic neuroendocrine tumors (NETs) usually do not respond to radiation, and therefore it is rarely used to treat these tumors. However, it can be used in case of pancreatic NETs that have spread to the bone and other tissues. Furthermore, the typical radiation treatment utilized for the treatment of the
ACCEPTED MANUSCRIPT exocrine pancreatic malignancies is External Shaft Radiation Treatment that focuses the radiation on the cancer from a machine outside the body. Radiation treatment is typically
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associated with different side effects, like skin changes in areas getting radiation, nausea
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but not the least increased risk of severe infection.
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and vomiting, diarrhea, fatigue, poor appetite, weight loss, lower blood counts and last
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Clinical Trials in Pancreatic Cancer
The chemotherapy drug, Gemcitabine, has been a standard initial treatment for patients
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with metastatic pancreatic cancer for over 15 years [86]. Various clinical trials have tried new medications, either alone or in combination with Gemcitabine (Table 1); however,
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the advancement is moderate amid the most recent decade [88-109, 111]. Gemcitabine
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alone or in combination with Capecitabine or Erlotinib remained the favored systemic
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treatment alternatives until 2010 [88-109]. Since 2010, use of FOLFIRINOX has increased both in metastatic and locally advanced cancer [110, 111]. Various drugs and combinations have been evaluated in the last couple of years, and some of them have shown promising results. Sunitinib and Everolimus have shown significant improvement in survival. Sunitinib treatment showed median progression-free survival of 11.4 months as compared with 5.5 months for patients who received the placebo. On the other hand, the patients receiving Everolimus showed median progression-free survival of 11 months as compared with 4.6 months for patients who received the placebo. Although these drugs have shown promising results, severe side effects as anemia and neutropenia were also observed.
ACCEPTED MANUSCRIPT Combination of Nab-Paclitaxel (Abraxane®), a form of the chemotherapy drug Paclitaxel bound to the human protein albumin and contained in nanoparticles, and Gemcitabine
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(Gemzar®) was also investigated in an international randomized phase III trial showing
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improved survival [112]. Patients who received the drug combination had a median overall survival of 8.5 months, compared with 6.7 months for patients treated with
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gemcitabine alone [112]. FDA approved therapy to treat patients with metastatic
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pancreatic cancer based on the results of the MPACT trial. Some other combinations, such as, gemcitabine with gamma-secretase inhibitor (MK-0752) or FG-3019 (a human
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monoclonal antibody that suppresses connective tissue growth factor), have also shown
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promising results [113].
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Herbal products, cancer prevention, and pancreatic cancer
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The relation between the consumption of certain dietary herbals and a reduced risk of cancer is becoming evident as many epidemiological and pre-clinical studies have shown the effect of herbals on health [114]. In the past few years, the cancer chemoprevention approach is directed towards polyphenols and their health-related properties and a wide range of dietary constituents show potential biological activities [114]. Studies in this line on cell/animal models and human epidemiological trials have shown the potential of dietary polyphenols as anti-carcinogenic agents. The reports have shown that phenolic compounds have the capability to inhibit the molecular events in the cancer initiation, promotion, and progression stages. They may increase the expression of pro-apoptotic components in initiated proliferating cells and thereby prevent or delay tumor development. Although it seems that phenolic compounds induce apoptosis in a precise manner in cancer cells but in some human studies no promising results were obtained. A
ACCEPTED MANUSCRIPT Cohort Study of Diet and Cancer in Netherlands suggested no effect of the consumption of black tea on the risk for colorectal, stomach, lung and breast cancers [115]. A similar
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study was performed in Japan involving more than 25,000 stomach cancer patients with a
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similar observation i.e. no association of consumption of green tea with gastric cancer risk [116]. Some other studies on different types of cancer also indicated the same
SC
conclusion [117-119]. On the contrary, a decreased risk for the different types of cancer
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these phenolic compounds [118-122].
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has been reported after the consumption of flavonoids or certain foods or drinks rich in
The use of herbals in the treatment of pancreatic cancer is a novel approach and is
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continuously gaining the attention of investigators. Previous research in this area was
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focused on inducing apoptosis but recently these herbals have been used in the targeting of other key pathways of cell survival, angiogenesis, metastasis, and differentiation. Easy
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availability and less or no toxicity even at higher doses have made them the preferable choice over other cancer chemopreventive options (Fig. 2). Resveratrol
Resveratrol, a phytoalexin, is commonly found as an ingredient in red wine, skins of grapes, peanuts and so forth. It possess anti-tumorigenic, anti-inflammatory, and antioxidant properties [123]. Its preventive role against cancers, cardiovascular diseases, and various neurological disorders has been widely reported [124-126]. Hydroxylation of resveratrol by CYP1B1 generates two major metabolites namely piceatannol and 3,4,5,4’-tetrahydroxystilbene that substantially contribute to its chemopreventive activities by inhibiting tyrosine kinase and inducing apoptosis [127-129].
ACCEPTED MANUSCRIPT Chemopreventive effects of resveratrol against various cancers have been extensively investigated in both in vitro and in vivo. It has been shown to have anti-tumor activity by
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inhibiting angiogenesis, endothelial cell migration, tumor formation and by blockage of
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oxygen free radical formation [130-132] (Table 2). Due to its lipophilic nature, it readily crosses the plasma membrane and establishes dynamic homeostasis by inhibiting the
SC
phase I (mainly CYP450s) and inducing phase II enzymes (UDP-glucuronosyl
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transferase, NAD(P)H quinone oxidoreductase, and glutathione-s-transferases) during stress conditions [133-138]. In cancerous cells, it inhibits the expression of inducible
MA
nitric oxide (NO) synthase and NO production [139]. It also inhibits the formation of a preneoplastic lesion in mouse mammary glands and proliferation of a variety of cancer
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cells in culture including, human colon, breast, and prostate cancer cells [140-143]. Resveratrol sensitizes a broad spectrum of tumors including lung carcinoma, acute
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myeloid leukemia, promyelocytic leukemia, multiple myeloma, prostate cancer, oral epidermoid carcinoma, and pancreatic cancer.
Zhou et al. showed that it enhances
caspase-3 activation and p53 and p21 expression in capan-2 and colo357 pancreatic cancer cell lines [144]. A recent approach, using human pancreatic CSCs (CD133+CD44+CD24+ESA+), showed that resveratrol sensitizes and inhibits the growth and development of pancreatic cancer lesion in KrasG12D mice [10]. This study further showed that the resveratrol inhibits pluripotency maintaining factors (Nanog, Sox-2, cMyc and Oct-4), drug resistance gene ABCG2, CSC's migration, invasion, self-renewal, and components of EMT (Zeb-1, Slug, and Snail) [10]. Resveratrol inhibits cell growth, proliferation and expression of the anti-apoptotic proteins Bcl-2, Bcl-xL, and XIAP and induces apoptosis, cell cycle arrests, caspases and pro-apoptotic gene Bax in pancreatic
ACCEPTED MANUSCRIPT cancer cell lines [145]. Additionally, resveratrol has been found to suppress proliferation and anchorage-independent growth of pancreatic cancer by inhibiting leukotriene B4
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(LTB4) production and expression of the LTB4 receptor 1 (LTB4R1) [146]. It is
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remarkable that LTB4 is a hydrolysis product of the leukotriene A4 (LTA4), and the process is catalyzed by LTA4 hydrolase, a known target for prevention and therapy of
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cancers including PC [147]. Resveratrol can directly bind to leukotriene A4 hydrolase
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(LTA-4H) and inhibit its activity and, therefore, LTB4 production [146].
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Curcumin
Curcumin is one of the most commonly used and highly investigated phytochemical.
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During the last decade, our understanding of its therapeutic potential and the multiple
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mechanisms by which it offers chemoprevention against various cancers has been
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increased [148] (Table 3). The various pharmacological effects of curcumin include apoptotic, anti-proliferative, anti-oxidant, and anti-angiogenic properties. The previous studies have highlighted that curcumin targets multiple signal transduction pathways and that it suppresses a number of essential elements in cellular signaling pathways, for example, phosphorylation catalyzed by protein kinases, c-Jun-activated protein 1 (AP-1) activation and prostaglandin biosynthesis. It has also been found that curcumin potentiates radiotherapy in PC cure probably by involving selective regulation of radiotherapy-induced NF-κB [149]. Studies have shown that curcumin inhibits cell proliferation and induces apoptotic cell death mediated by PARP cleavage and Caspase-3 in MIAPaCa-2, Panc-1 and BxPC-3 pancreatic cancer cells [150]. Subramaniam et al. showed a significant reduction in tumor volume and
ACCEPTED MANUSCRIPT angiogenesis in curcumin treated tumor xenografts [151]. They further showed that curcumin inhibits cell proliferation, induces of G2-M arrest and apoptosis, enhances
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phosphorylation of checkpoint kinase 2 (Chk2) coupled with higher levels of nuclear
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cyclin B1 and Cdc-2, and increases expression of cyclooxygenase-2 (COX-2) [151]. Curcumin also inhibits ERK activity and suppresses EGFR and Notch-1 signaling leading
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to increased apoptosis in pancreatic cancer. Glienke et al. showed that incubation with
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curcumin results in down-regulation of Wilms' tumor gene 1 (WT1; a gene frequently expressed in pancreatic cancer) in a dose-dependent manner [152]. Additionally,
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curcumin has been shown to restrain STAT3 and induce apoptosis by inhibiting the
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expression of the anti-apoptotic gene Survivin/BIRC4 in pancreatic cancer cells [153].
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Recently Bar-Sela et al. reviewed the accomplished and continuing clinical trials with curcumin as an anticancer agent [154]. In one trial, 17 patients were treated with the oral
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dose of 8 gm/day of curcumin in combination with Gemcitabine. Although the results showed that this combined treatment is tolerable in patients; nevertheless, it has been suggested to reduce the dose of curcumin [155]. Dhillon et al. used only curcumin as the 1st line treatment for the 25 patients. They found that curcumin down regulates the expression of NFκB, COX-2, and the phosphorylation of STAT3 in peripheral blood [156]. In spite of these encouraging results, extensive clinical trials are needed before drawing any conclusion. Epigallocatechin gallate (EGCG) Epigallocatechin gallate (EGCG) is a most extensively studied catechin and the major polyphenol present in green tea. Various studies have shown that EGCG offers protection
ACCEPTED MANUSCRIPT against pancreatic cancer among the other tumors (Table 4); however, the exact molecular mechanism by which EGCG suppresses human pancreatic cancer cell
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proliferation is unclear. Kürbitz et al. showed anticancer properties of EGCG on human
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pancreatic ductal adenocarcinoma (PDAC) cells PancTu-I, Panc1, Panc89 and BxPC3 in vitro [157]. They found that EGCG inhibits proliferation of PDAC cells in a dose- and
SC
time-dependent manner. The protein expression analysis performed with PancTu-I cells
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evidently showed EGCG-mediated modulation of cell cycle regulatory proteins (cyclins, cyclin-dependent kinases, and inhibitors). The study further stated that EGCG inhibits
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TNFα-induced activation of NF-κB and consequently secretion of pro-inflammatory and invasion-promoting proteins like IL-8 and uPA [157]. Moreover, previous studies have
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demonstrated that EGCG decreases cell adhesion ability on micro-pattern dots, accompanied by dephosphorylation of both focal adhesion kinase and insulin-like growth
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factor-1 receptor (IGF-1R) in AsPC-1 and BxPC-3 cells [158] [159] [64]. EGCG has been also found to aid retained activation of MAPK signaling, suppressed growth, reduced cell viability, and increased apoptosis in these cells in a dose-dependent manner [158].
Effects of EGCG on heat shock proteins were also investigated. A study by Li Y et al. showed that the binding of EGCG to Hsp90 impairs the association of Hsp90 with its cochaperones, thereby inducing degradation of Hsp90 client proteins (Akt, Cdk4, Raf-1, Her-2, and pERK) consequently anti-proliferating effects in pancreatic cancer cells [160]. Basu and Haldar showed that EGCG causes the disappearance of intact 21 kDa Bid protein and induces activation of caspase-8 leading to cell death in MIA PaCa-2 cells [161]. Further, involvement of transmembrane extrinsic signaling in this polyphenol
ACCEPTED MANUSCRIPT triggered pancreatic carcinoma cell death was confirmed by RNase protection assay that clearly showed up-regulation of the members of death receptor family [161] [160].
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Shankar et al. examined the role of EGCG in inhibiting growth, invasion, metastasis and
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angiogenesis of human pancreatic cancer cells in a xenograft model system [162]. They
SC
found that EGCG inhibits viability, capillary tube formation, and migration of HUVEC. Additionally, they observed EGCG-mediated inhibition of proliferation (Ki-67 and
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PCNA staining), angiogenesis (vWF, VEGF and CD31) and metastasis (MMP-2, MMP-
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7, MMP-9 and MMP-12), and induction of apoptosis (TUNEL), caspase-3 activity and growth arrest (p21/WAF1) in vivo [162]. They also found a significant reduction in the
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circulating vascular endothelial growth factor receptor 2 (VEGF-R2) positive endothelial
Genistein
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treatment [162].
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cells, ERK activity, and induction of p38 and JNK activities in vivo following EGCG
Genistein is found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea, in the medicinal plant, Flemingia vestita, and coffee [159, 160, 163-165]. It has multiple effects in living cells, such as activation of PPARs, estrogen receptor-β, Nrf2 anti-oxidative response, stimulation of autophagy and inhibition of several tyrosine kinases, topoisomerase, and mammalian hexose transporter GLUT-1 [73, 166-174]. Genistein also affects tumor formation, cell multiplication and differentiation, angiogenesis, and signaling triggered by growth factors [175-184]. The most critical activity that contributes to the chemopreventive potential of genistein is tyrosine kinase inhibition, mostly of epidermal growth factor receptor EGFR. Additionally, the inhibitory
ACCEPTED MANUSCRIPT effect of genistein on DNA topoisomerase II is also a major contributor to its cytotoxic activity [170, 172].
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Genistein inhibits cell growth, clonogenicity, cell migration and invasion, EMT
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phenotype, and formation of pancreatospheres consistent with reduced expression of
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CD44 and EpCAM [185]. Wang et al., showed that genistein restricts pancreatic cancer cell invasion by inhibiting cell growth and inducing apoptosis along with attenuation of
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FoxM1 and its downstream genes (survivin, Cdc25a, MMP-9, and VEGF) [186].
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Sulforaphane
Sulforaphane has been reported to inhibit the growth of established tumors and prevent
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chemically induced cancers in animal models [187-189] (Table 5). It has been shown to inhibit Akt pathway in ovarian, prostate and colorectal cancers [189-191] and down-
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regulate β-catenin in HeLa and HepG2 cells [192]. Additionally, it also targets breast cancer stem/progenitor cells effectively in both in vitro and in vivo conditions [193]. The studies have shown that recipient NOD/SCID mice inoculated with tumor cells derived from sulforaphane-treated primary xenograft failed to develop tumor growth, whereas control tumor cells quickly generate large tumors [194]. Furthermore, sulforaphane has also been shown to inhibit the self-renewal capacity of pancreatic CSCs. Srivastava et al., showed that inhibition of Nanog enhances the inhibitory effects of sulforaphane on the self-renewal capacity of CSCs [195]. Sulforaphane induces apoptosis by activating caspase-3 and inhibiting the expression of Bcl-2 and XIAP, as well as phosphorylation of FKHR. Additionally, sulforaphane is suggested to block signaling involved in early metastasis by inhibiting the expression of
ACCEPTED MANUSCRIPT proteins involved in the epithelial-mesenchymal transition (beta-catenin, vimentin, TWIST1, and ZEB1) [195]. Additionally, sulforaphane, in combination of with TRAIL,
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has been suggested to be a promising strategy for targeting pancreatic tumor initiating
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cells (TICs). It has been found that it could abrogate the resistance of pancreatic TICs to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by interfering with
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Garlic
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TRAIL-activated NF-κB signaling [196].
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Garlic has been traditionally used for varied human ailments around the world. Epidemiological observations and preclinical studies, both in cell and animal models,
D
suggest the anti-carcinogenic potential of garlic and its constituents [197]. Chemical
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analysis revealed that the protective effects of garlic are due to the presence of
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organosulfur compounds mainly allyl derivatives [197]. Additionally, it modulates the activity of several metabolizing enzymes involved in the activation and detoxification of carcinogens and inhibits DNA adduct formation. It possess anti-oxidative and free radicals scavenging properties and regulates cell proliferation, apoptosis, and immune responses. Recent data suggest that garlic also modulates cell-signaling pathways to avoid proliferation of unwanted cells thereby imparting strong cancer chemopreventive, as well as cancer therapeutic effects [197]. Benzyl Isothiocyanate (BITC) Due to their capability to induce apoptosis, modulate signaling pathways and inhibit angiogenesis, isothiocyanates (ITCs) have shown a great promise as chemopreventive agents against various tumors in recent years [198]. Benzyl isothiocyanate (BITC) is a
ACCEPTED MANUSCRIPT major ITC compound present in cruciferous vegetables. BITC suppresses the initiation and progression of a variety of cancers including lung, esophageal, forestomach, urinary
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bladder, mammary, liver, colon, and pancreatic tumors [198-203]. Various preclinical
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and mechanistic studies have supported the anticancer efficacy of BITC, and it has been found to suppress the growth of human pancreatic cancer cells both in vitro and in vivo.
SC
BITC is reported to induce G(2)/M phase cell cycle arrest, and apoptotic cell death in
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pancreatic cancer cell/animal models [204-207]. The apoptotic potential of BITC is attributed to its capability to activate MAPK family members i.e. ERK, JNK and P38 by
MA
catalyzing their phosphorylation at Thr202/Tyr204, Thr183/Tyr185, and Thr180/Tyr182 respectively in a dose-dependent manner [206]. Additionally, the potential to inhibit the
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D
phosphorylation and expression of NF-kB most likely via inhibition of HDAC1/HDAC3, is suggested to be another contributory factor to the apoptotic potential of BITC [204].
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Furthermore, it has been found to inhibit angiogenesis and metastasis by suppressing VEGF and MMP-2 expression in pancreatic cancer cells [208]. Recently Boreddy et al., showed that BITC offers protection against pancreatic tumor growth by effectively containing STAT-3 and HIF-1α and VEGF expression in BxPC-3 and PanC-1 pancreatic cancer cells [208]. It reduces the phosphorylation of PI3K, Akt, Pdk1, mTOR, FoxO1, and FoxO3a and increases apoptosis in tumor xenograft mouse model. BITC treatment also decreases the binding of FoxO1 with 14-3-3 protein suggesting it’s nuclear retention and subsequent elevation of FoxO-responsive proteins involved in apoptosis (Bim) and cell cycle arrest (p27 and p21) [209]. BITC has also been shown to sensitize pancreatic tumors for radiotherapy. BITC treatment in a combination of X-rays or gamma-irradiation reduces cell survival as
ACCEPTED MANUSCRIPT compared with individual (X-rays or gamma-irradiation) exposure in pancreatic cancer cells. This effect is suggested to be due to the inhibition of cell proliferation and anti-
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apoptotic genes like XIAP/IAP, and augmentation of apoptosis protease activating factor-
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1 (Apaf-1) triggered by BITC [208]. It is remarkable that Apaf-1 is essential for activation of caspase-9 in stress-induced apoptosis [208].
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Piperlongumine:
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Piperlongumine (PL) is an alkaloid found in the fruits of long pepper plants that displays
MA
potent growth-inhibitory properties in a variety of cancer cell lines and various animal models. It has been identified to target cancer cells selectively over normal cells through
D
an ROS-dependent mechanism in a cell-based small-molecule screening and quantitative
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proteomics approach [210]. It increases ROS levels and cancer-selective cell death by directly binding and inhibiting the antioxidant enzyme glutathione S-transferase pi 1
AC CE P
(GSTP1) [210, 211]. Raj et al., have shown that PL selectively targets pancreatic cancer cells, PANC-1, and MIA PaCa-2- both of which harbor mutated K-ras [210]. A recent study by Dhillon et al. further supported this finding and suggested that PL also targets BxPC-3 pancreatic cancer cells that contain wild-type K-ras [212]. They further showed the anti-cancer effects of PL in vivo. PL reduces tumor volume, increases oxidative DNA damage (8-OHdGhigh), and reduces proliferation (Ki-67low) in nude mice xenografts for PANC-1 [212]. Conclusion and future perspectives Pancreatic cancer is continuously posing a challenge to the clinicians and researchers. We are still relying on the old traditional therapies. The major drawback of current therapy is
ACCEPTED MANUSCRIPT their unilateral actions on one or two pathways whereas the approach should be to target several targets simultaneously. The combination therapy is a right approach in this
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direction, but associated side effects are a major concern. Since the small population of
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pancreatic CSCs is mostly responsible for the pathogenesis of pancreatic cancer, an efficient, targeted therapy for pancreatic CSCs is also an excellent approach. However,
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the problem is the resistance of pancreatic CSCs against conventional treatment but still
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developmental pathways such as the hedgehog, Wnt, Notch, etc. can be targeted.
MA
Flavonoids have emerged as potential chemopreventive candidates for cancer treatment, especially by their ability to induce apoptosis. These can interfere with the initiation,
D
development and progression of cancer by the modulation of cellular proliferation,
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differentiation, apoptosis, angiogenesis, and metastasis. Flavonoids have been shown to target cancer cells specifically with no or insignificant effects on healthy cells in vitro.
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Nevertheless, some studies suggest to include experimental conditions (dose, cell type, culture conditions and treatment length) while interpreting the results of in vitro studies because the biological outcome can be affected. Since the apparent phenomenon is a result of complex interaction of different cellular events, the mechanisms for inducing the apoptosis of these polyphenols may overlap with other signaling cascades. Therefore, the promising strategy could be the promotion of programmed cell death through the modulation of different proteins in other pathways that can contribute to cell death. Flavonoids exhibit some characteristic effects, for example, induction of apoptosis, activation of caspases, down-regulation or up-regulation of Bcl-2 family members, induction of cell cycle arrest and inhibition of survival/proliferation signals. Moreover, the effects of these plant products on pancreatic cancer initiation, promotion and
ACCEPTED MANUSCRIPT metastasis has also discussed in the light of available literature. The results from in vitro experiments constitute a valuable tool for elucidating the pathways involved in the
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overall carcinogenesis process, although these cannot be directly extrapolated to clinical
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effects. The best thing about herbal products is that they target multiple signaling events simultaneously; however; more studies are needed to understand clearly the mechanisms
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of action of flavonoids as modulators of cell survival and apoptosis.
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Acknowledgments
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We acknowledge our lab members for critical reading of the manuscript, insightful discussions, and valuable advice. The project was funded by the National Institutes of
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Health (RKS) and The VA Merit Award (SS).
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Table 1: List of some of the completed clinical trials on pancreatic cancer (Source: www. ClinicalTrials.gov) Rank
Interventions
NCT Number
1 2
Drug: RAD001 Drug: Gemcitabine|Drug: Albuminbound paclitaxel Drug: gemcitabine hydrochloride|Drug: imatinib mesylate Dietary Supplement: genistein|Drug: erlotinib hydrochloride|Drug: gemcitabine hydrochloride Drug: Ixabepilone|Drug: Cetuximab Biological: cetuximab|Drug: docetaxel|Drug: irinotecan hydrochloride Drug: alvocidib|Drug: docetaxel
Drug: bortezomib|Drug: carboplatin|Other: laboratory
3
4
5 6
7
8
Conditions
NCT00409292 NCT00398086
Enroll ment 33 67
NCT00161213
44
Pancreatic Cancer
NCT00376948
20
Pancreatic Cancer
NCT00383149 NCT00042939
58 94
Metastatic Pancreatic Cancer Pancreatic Cancer
NCT00331682
10
NCT00416793
9
Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Acinar Cell Adenocarcinoma of the Pancreas|Duct Cell
Pancreatic Cancer Metastatic Pancreatic Cancer
ACCEPTED MANUSCRIPT
Drug: bevacizumab [Avastin] Drug: Erlotinib, escalating dose|Drug: Erlotinib, standard dose|Drug: Gemcitabine
NCT01214720 NCT00652366
607 467
12
Drug: Ipilimumab|Biological: Pancreatic Cancer Vaccine Biological: cixutumumab|Drug: erlotinib hydrochloride|Drug: gemcitabine hydrochloride Drug: Gemcitabine|Drug: Erlotinib|Drug: Sorafenib Biological: bevacizumab|Drug: erlotinib hydrochloride|Other: laboratory biomarker analysis Drug: Capecitabine|Drug: Docetaxel Drug: Abraxane Drug: gamma-secretase/Notch signaling pathway inhibitor RO4929097
NCT00836407
30
NCT00617708
134
19 20
21 22 23
24
25
26 27 28
29
SC
Pancreatic Cancer
NCT00365144
36
Pancreatic Cancer
NCT00290693 NCT00691054 NCT01232829
45 20 18
NU
45
Drug: Lenalidomide|Drug: Gemcitabine Drug: sorafenib tosylate|Drug: gemcitabine hydrochloride|Other: laboratory biomarker analysis Drug: GSK1120212|Drug: Gemcitabine|Drug: Placebo Drug: Gemcitabine|Drug: AG013736|Drug: Gemcitabine Drug: dasatinib|Procedure: laboratory biomarker analysis|Procedure: physiologic testing Drug: gemcitabine|Drug: placebo|Drug: Erlotinib|Drug: apricoxib Drug: AG-013736|Drug: Gemcitabine|Drug: Gemcitabine|Drug: placebo Drug: Albumin-bound paclitaxel|Drug: Gemcitabine Drug: cohort 1|Drug: cohort 2|Drug: cohort 3|Drug: cohort 4 Drug: gemcitabine hydrochloride|Drug: tanespimycin
NCT00837031
72
Pancreatic Cancer Pancreatic Cancer Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Metastatic Pancreatic Cancer
NCT00114244
52
Stage IV Pancreatic Cancer
NCT01231581
160
Cancer
NCT00219557
111
Pancreatic Neoplasms
NCT00474812
49
NCT00709826
109
Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Pancreatic Cancer|Metastatic Pancreatic Cancer
NCT00471146
630
Carcinoma, Pancreatic Ductal
NCT00844649
861
Metastatic Pancreatic Cancer
NCT00439179
27
Metastatic Pancreatic Cancer
NCT00577889
21
Drug: PCI-27483|Drug: Gemcitabine
NCT01020006
42
Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Pancreatic Cancer|Ductal Adrenocarcinoma|Exocrine Pancreatic Cancer
MA
16 17 18
Stage IV Pancreatic Cancer
NCT00696696
D
15
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14
AC CE P
13
Pancreatic Cancer
RI
9 10
Adenocarcinoma of the Pancreas|Stage IV Pancreatic Cancer Pancreatic Cancer Pancreatic Cancer
PT
biomarker analysis
ACCEPTED MANUSCRIPT
37
38 39
41
42 43 44 45
Drug: Cetuximab|Drug: Gemcitabine|Drug: Oxaliplatin|Drug: Capecitabine|Radiation: Radiotherapy Drug: Gemcitabine
NCT00338039
69
Metastatic Pancreatic Adenocarcinoma Pancreatic Cancer
NCT00390182
38
Biological: DTA-H19 Drug: Fentanyl sublingual spray|Drug: Placebo Drug: Avastin|Drug: Tarceva|Radiation: Radiation Therapy Drug: Gemcitabine|Drug: Sunitinib
NCT00711997 NCT00538850
9 130
Gastrointestinal Neoplasms|Ovarian Neoplasms Pancreatic Neoplasms Cancer
NCT00735306
12
Pancreatic Cancer
NCT00556049
72
RI
PT
367
SC
36
NCT01124786
NU
34 35
Pancreatic Neoplasms
NCT00661830
103
Renal Cell Carcinoma|Neoplasm Metastases Adenocarcinoma
NCT00448136
83
Neoplasms
Drug: Avastin (Bevacizumab, RHUMAB VEGF)|Drug: Capecitabine|Radiation: Radiation Therapy Drug: Sunitinib
NCT00113230
25
Rectal Cancer
NCT01121562
12
Drug: RAD001|Drug: Octreotide Depot Drug: Sunitinib malate|Procedure: Hepatic Artery Embolizations Other: Cocoa Polyphenols
NCT00113360
67
NCT00434109
39
NCT01617603
62
Pancreatic Neuroendocrine Tumors Neuroendocrine Carcinoma|Islet Cell Carcinoma Neuroendocrine Tumor|Islet Cell Tumor Diabetes Type 2
Drug: Gemcitabine|Drug: Placebo|Drug: Sorafenib Drug: bevacizumab [Avastin]|Drug: 5 FU|Drug: Streptozotocin|Drug: Xeloda
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33
142
D
32
NCT00637247
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31
Drug: imexon in combination with gemcitabine|Drug: imexon placebo + gemcitabine Drug: CO-1.01|Drug: Gemcitabine
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30
ACCEPTED MANUSCRIPT Table 2: Summary of recent findings showing chemopreventive potential of resveratrol against pancreatic cancer Effect
Reference
MIA PaCa-2 cells
Inhibits proliferation and induces apoptosis
Panc-28 and Hs766T
Increases calcium levels and prevents migration of TG2-
cells
expressing cells
Capan-2 cells
Inhibits tumor growth, induced apoptosis, and up-regulated Bax
[213]
[214]
MA
NU
SC
RI
PT
Cells
[215]
Inhibits cell proliferation, migration, and induces expression of
TE
BxPC-3 and Panc-1
D
and VEGF-B expression
[216]
EMT-related genes (E-cadherin, N-cadherin, vimentin, MMP-2,
PANC-1,
AC CE P
and MMP-9)
CFPAC-1,
Inhibits viability and miR-21 expression and increases Bcl2
[217]
and MIA Paca-2 cells
expression
BxPC-3 and Panc-1
Inhibits the growth Gli1, Ptc1, CCND1, and BCL-2
[218]
PANC-1, MIA PaCa-
Up-regulates p21/CIP1, p27/KIP1, Bim, activates csapase-3,
[219]
2, Hs766T, and AsPC-
reduces phosphorylation of ERK, PI3K, Akt, FoxO1, and
1
FoxO3a
ACCEPTED MANUSCRIPT Table 3: Summary of recent findings showing chemopreventive potential of curcumin against pancreatic cancer Effect
MIA PaCa-2
Inhibits the proliferation and enhances apoptosis in MIA PaCa-2 (tumor
xenograft model)
RI
mouse
[220]
cells and inhibits tumor growth and the expression of the transcription nuclear factor NF-κB and NF-κB-regulated gene
SC
and
Reference
PT
Cells/ animals
the
NU
products in xenograft mouse model MiaPaCa-2 and Panc-1
Down-regulates
expression
of
miR-221
resulting
in
cells
upregulation of PTEN, p27(kip1), p57(kip2), and PUMA leading
[221]
and
Inhibits cell proliferation, reduces tumor growth and angiogenesis
mouse
(tumor
xenograft model)
[222]
as determined by a reduced number of blood vessels and
D
MIA PaCa-2
MA
to the inhibition of cell proliferation and migration
decreased expression of vascular endothelial growth factor and
TE
annexin A2 proteins
Activates TNFR, CASP 8, CASP3, BID, BAX, and down-
2
regulates NFκB, NDRG 1, and BCL2L10 gene
AC CE P
BxPC-3 and MiaPaCa-
TGF-β1-stimulated
[223]
Inhibits proliferation, induces apoptosis and reverses the EMT
[224]
AsPC-1 and MiaPaCa-
Decreases
[225]
2
formation of pancreatospheres, invasive cell migration, and CSC
PANC-1 cells
pancreatic
cancer
cell
survival,
clonogenicity,
function AsPC-1,
MiaPaCa-2,
Panc-1, human
and
mouse cancer cells
Inhibits tumor growth through mitotic catastrophe by increasing
BxPC-3
the expression of RNA binding protein CUGBP2, thereby
Pan02
inhibiting the translation of COX-2 and VEGF expression
pancreatic
[151]
ACCEPTED MANUSCRIPT Table 4: Summary of recent findings showing chemopreventive potential of EGCG against pancreatic cancer Reference
PANC-1
Suppresses
proliferation
and
PT
Effect
induces
apoptosis,
RI
Cells/ animals
[226]
modulates the PI3K/Akt/mTOR signaling pathway Regulates RKIP/ERK/NF-κB and/or RKIP/NF-κB/Snail
SC
AsPC-1 cells
[227]
and inhibits invasive metastasis c
nude
mice
(tumor
xenograft model)
Inhibits pancreatic cancer orthotopic tumor growth,
NU
Balb
[162]
angiogenesis, and metastasis, inhibits PI3K/Akt and ERK
Colo357
human
pancreatic
adenocarcinoma cells
MA
pathways and activation of FKHRL1/FoxO3a With PGHS-2-specific inhibitor celecoxib, synergistically
[228]
diminishes metabolic activity via apoptosis induction and release
of
pro-angiogenic
vascular
D
down-regulates
TE
endothelial growth factor (VEGF) and invasiveness-
PANC-1
AC CE P
promoting matrix metalloproteinase (MMP)-2
Inhibits HIF-1α protein expression, P-gp mRNA and
[229]
protein levels and cell proliferation
AsPC-1 and PANC-1
Suppresses the growth, invasion, and migration, induces
[230]
apoptosis by interfering with the STAT3 signaling pathway and enhances the therapeutic potential of gemcitabine and CP690550
Human pancreatic cancer stem
Inhibits Nanog, c-Myc and Oct-4 expression, self-
cells
renewal, proliferation, EMT, components of Shh pathway
(CD133+/CD44+/CD24+/ESA+)
(smoothened, patched, Gli1 and Gli2) and Gli transcriptional activity, and induces apoptosis by inhibiting Bcl-2 and XIAP and activating caspase-3
[231]
ACCEPTED MANUSCRIPT Table 5: Summary of recent findings showing chemopreventive potential of sulforaphane against pancreatic cancer Effect
Established BxPc-3 and AsPC-1
Increases Cx43 and E-cadherin levels, inhibits c-Met and
PDA cell lines and immortalized
CD133, improved the functional morphology and
CRL-4023
communication of gap junctions.
human PDA cells
Inhibits cell viability and NF-κB DNA binding activity,
[233]
NU
MIA PaCa-2 and Panc-1
[232]
RI
SC
hTERT-HPNE
Reference
PT
Cells/ animals
induces cell apoptosis by activation of caspase-3 and PARP cleavage, increases pERK1/2, c-Jun, p38 MAPK,
MA
p53 protein expression when used in combination with aspirin and curcumin NOD/SCID/IL2Rgamma
mice
components,
D
(tumor xenograft model)
Inhibits growth of tumors, expression of Shh pathway EMT,
pluripotency
[85]
maintaining
TE
transcription factors, angiogenic markers and induces apoptosis Inhibits CSC’s derived spheres, components of Shh
cells
human
pathway and Gli transcriptional activity, expression of
pancreatic cancer stem cells
pluripotency maintaining factors (Nanog and Oct-4) as
(CD133+/CD44+/CD24+/ESA+)
well as PDGFRα and Cyclin D1
Pancreatic
Disrupts protein-protein interaction in Hsp90 complex for
AC CE P
Human normal pancreatic stem (HPSC)
and
cancer
mouse model
xenograft
[84]
[234]
its chemopreventive activity
MIA-PaCa2
Potentiates the inhibitory effects of gemcitabine and 5-
[235]
flurouracil on clonogenicity, spheroid formation, ALDH1 activity, Notch-1 and c-Rel expression
PANC-1, AsPC-1
MIA
PaCa-2
and
Inhibits cell proliferation, colony formation, phosphorylation of Akt and ERK, activates FoxO transcription factors and induces apoptosis
[79]
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ACCEPTED MANUSCRIPT Disclosure of Potential Conflicts of Interest
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The authors have declared that no Conflicts of Interest exist.
ACCEPTED MANUSCRIPT Highlights
Pancreatic cancer (PC) is a complex hereditary disease with high mortality
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rate.
PC exhibits resistance against chemo- and radiotherapy.
PC stem cells contribute greatly to its resistance against chemo- and
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Herbal products target multiple pathways involved in carcinogenesis
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radiotherapy.
simultaneously.
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cure.
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Solution involving herbals may be a smart thought for better results in PC
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S0304-419X(15)00035-9 doi: 10.1016/j.bbcan.2015.04.003 BBACAN 88039
To appear in:
BBA - Reviews on Cancer
Received date: Revised date: Accepted date:
30 January 2015 28 April 2015 30 April 2015
Please cite this article as: Divya Singh, Ghanshyam Upadhyay, Rakesh K. Srivastava, Sharmila Shankar, Recent Advances in Pancreatic Cancer: Biology, Treatment, and Prevention, BBA - Reviews on Cancer (2015), doi: 10.1016/j.bbcan.2015.04.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Recent Advances in Pancreatic Cancer: Biology, Treatment, and Prevention
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Divya Singh1, Ghanshyam Upadhyay1*, Rakesh K. Srivastava2*, Sharmila Shankar2,3*
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Department of Biology, City College of New York, 160 Convent Avenue, New York, NY-10031 Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128.
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Department of Pathology, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108.
Email:
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[email protected] [email protected]
[email protected] [email protected]
*Corresponding author: Dr. Rakesh Srivastava ([email protected]) Dr. Sharmila Shankar ([email protected])
ACCEPTED MANUSCRIPT Abstract Pancreatic cancer (PC) is the fourth leading cause of cancer-related death in United
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States. Efforts have been made towards the development of the viable solution for its
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treatment with constrained accomplishment because of its complex biology. It is well
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established that pancreatic cancer stem cells (CSCs), albeit present in a little count, contribute incredibly to PC initiation, progression, and metastasis. Customary chemo and
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radiotherapeutic alternatives, however, expands general survival, the related side effects
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are the significant concern. Amid the most recent decade, our insight about molecular and cellular pathways involved in PC and role of CSCs in its progression has increased
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enormously. Presently the focus is to target CSCs. The herbal products have got much
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consideration recently as they, usually, sensitize CSCs to chemotherapy and target molecular signaling involved in various tumors including PC. Some planned studies have
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indicated promising results proposing that examinations in this course have a lot to offer for the treatment of PC. Although preclinical studies uncovered the importance of herbal products in attenuating pancreatic carcinoma, limited studies have been conducted to evaluate their role in clinics. The present review provides a new insight to recent advances in pancreatic cancer biology, treatment and current status of herbal products in its anticipation.
ACCEPTED MANUSCRIPT Abbreviations: Oct4: octamer-binding transcription factor 4; ABCG2: ATP-binding cassette sub-family
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G member 2; CXCR4; C-X-C chemokine receptor type 4; FGF: fibroblast growth factor;
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Frizzled-9: frizzled class receptor 9; Glut1: glucose transporter 1; Foxa2: forkhead box
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A2; Sox2: sex determining region Y box 2; Klf4: kruppel like factor 4; c-Myc: v-Myc avian myelocytomatosis viral oncogene homolog; FGF; fibroblast growth factor; ESA:
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epithelial-specific antigen; ALDH1: acetaldehyde dehydrogenases 1; ABCB1: ATP-
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binding cassette sub-family B member 1; MDR1: multidrug resistance protein 1; DCLK1: doublecortin-like kinase 1; Cdkn2a: cyclin-dependent kinase inhibitor 2a; Dpc4
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or Smad4: deleted in pancreatic carcinoma, locus 4; STAT3: signal transducer and
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activator of transcription 3; TNF-α: tumor necrosis factor α; MCP-1: monocyte chemotactic protein-1; EGF: epidermal growth factor; EGFR: epidermal growth factor
factor;
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receptor; PDGF: platelet-derived growth factor; G-CSF: granulocyte colony-stimulating GM-CSF:
granulocyte-macrophage
colony-stimulating
factor;
TGF-β
:
transforming growth factor beta; Chk2: checkpoint kinase 2; COX-2: cyclooxygenase-2; IGF-1R: insulin-like growth factor-1 receptor; VEGF: vascular endothelial growth factor; HIF1α: hypoxia inducible factor 1α; MMP: matrix metalloproteinase, TWIST1: Twistrelated protein 1; ICAM1: intercellular adhesion molecule 1; Bcl-2: B-cell lymphoma 2, Bcl-xL: B-cell lymphoma extra-large, Bad: Bcl-2-associated death promoter; Bak: Bcl-2 homologous antagonist/killer; Bax: Bcl-2-associated X protein; Mcl-1: induced myeloid leukemia cell differentiation protein; Pdx1: pancreatic and duodenal homeobox 1, uPA: urokinase-type plasminogen activator; uPAR: urokinase-type plasminogen activator receptor; MAPK: mitogen activated protein kinase; FoxO1: forkhead box O1; FoxO3:
ACCEPTED MANUSCRIPT forkhead box O3; PI3K: phosphatidylinositol 3-kinase; PARP: peroxisome proliferatoractivated receptor; PTEN: phosphatase and tensin homolog; PDGFRα: alpha-type
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platelet-derived growth factor receptor; IGF2R: insulin-like growth factor 2 receptor;
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ENG: endoglin, ALK1: activin receptor-like kinase 1; FKHRL1: forkhead box O3a; FKHR: forkhead box O1: AFX: forkhead box O4; TP53: tumor protein p53; TRAIL:
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tumor necrosis factor-related apoptosis-inducing ligand; Cdk4: cyclin-dependent kinase
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4; Raf-1: RAF proto-oncogene serine/threonine-protein kinase; Her-2: human epidermal growth factor receptor 2; EMT: endothelial to meseanchymal transition; DR: death
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receptor; EpCAM: epithelial cell adhesion molecule; vWF: von Willebrand factor; PCNA: proliferating cell nuclear antigen; Hsp: heat shock potein; XIAP: X-linked apoptosis
protein;
IAP:
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of
inhibitor
of
apoptosis
protein;
Pdk1:
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inhibitor
phosphoinositide-dependent kinase-1; mTOR: mammalian target of rapamycin; ERK:
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extracellular-signal-regulated kinases; JNK: c-Jun N-terminal kinases; HDAC: histone deacetylases; p38: P38 mitogen-activated protein kinases; ROS: reactive oxygen species
ACCEPTED MANUSCRIPT Introduction The burden of pancreatic cancer (PC) has continuously increased worldwide. It is a
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serious health concern and fourth leading cause of cancer-related death in United States
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of America [1, 2]. PC is described as a type of gastrointestinal tumor with a poor
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anticipation and a high level of danger and death rate [3]. More than 90% of pancreatic tumors have inception from the ductal epithelium of pancreas consequently termed as
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pancreatic ductal adenocarcinoma (PDAC). It is disturbing to see that frequency rate of
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the pancreatic tumor is relentlessly expanding in the western world [4]. The danger components for pancreatic growth incorporate smoking, obesity and high utilization of
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processed meat. Age is positively correlated with pancreatic cancer incidences, and the
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larger part of cases are diagnosed over the age of 60 [5]. The introductory indications of patients with PDAC are back agony and dyspepsia with additional disturbing
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manifestations like the new onset of diabetes, jaundice, and unconstrained profound vein thrombosis and weight reduction. When one begins perceiving, the tumor typically, spreads to the encompassing tissues or distant organs. For the tumors spotted in the head region of pancreas, the determination is actually productive and they are diagnosed relatively early because of biliary impediment. Nonetheless, the tumors in the body and tail of pancreas regularly stay asymptomatic until late in disease stage. Most of the patients (~80%) are identified with unresectable locally advanced or metastatic disease and the major cause is the delayed diagnosis and lack of specific blood or urine biomarkers to identify patients with increased risk of developing pancreatic cancer [6-9]. The routine diagnostics incorporate transabdominal ultrasound in the introductory
ACCEPTED MANUSCRIPT assessment of the jaundiced patient alongside computed tomography (CT) scan or magnetic resonance imaging (MRI).
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Despite the fact that the survival rate for most diseases has been increased lately in a
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couple of decades, little change is seen in the case of pancreatic cancer. The usual
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survival rate for pancreatic disease patients is under six months, and just 3% patients survive over 5-years [6-9]. The reason is attributed to various factors including silent
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nature in early stages, aggressive tumor biology, the low scope of surgical management,
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and lack of effective systemic therapies. Although, the current procedures including surgery, chemotherapy, radiation, and immunosuppressants, have made great advances in
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diminishing tumor frequencies and death rates, pancreatic cancer remains a continuing
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challenge to the researchers and treatment strategies at present utilized are not very encouraging [10]. There are exceptionally poor post-surgery survival rates even when the
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pancreatic tumor is surgically resected. Safety concerns related with these medications/techniques are likewise a significant issue for their accomplishment in the treatment of the disease [6-9]. The prevalent chemotherapeutic choices for the cancer treatment prolong the life of pancreatic cancer patients minimally, and the survival span in a large portion of the cases is not over one year. Since limited treatment choices are accessible, and it additionally shows resistance against chemo- and radiotherapies, it is important to find novel and viable methodologies for the treatment of pancreatic cancer [10]. Although the potential use of herbal components for the protection against various cancers began several decades ago, studies to understand the mechanism of their action at biochemical, genomic, and proteomic levels started very recently. Many plant products
ACCEPTED MANUSCRIPT that are rich sources of phytochemicals, such as triterpenes, flavonoids or polyphenols, are now established potent chemopreventive agents [11-15]. The phenolic substances are
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isolated from the wide range of vascular plants and have the ability to reduce and
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scavenge free radicals [16, 17]. Epidemiological studies have shown the reduced risk of pancreatic cancer by increased consumption of fruits and vegetables [18]. In the recent
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past, a number of preclinical studies have demonstrated various degrees of the efficacy of
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herbal products both in vitro and in vivo [18]. Certain dietary agents, for example, resveratrol and curcumin, have been demonstrated to potentiate the standard
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chemotherapy [18]. It has been observed that herbal products target different pathways simultaneously therefore any solution including these products may be a smart thought
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for better results. Many groups are working in this direction, and the outcomes are promising towards the improvement of new helpful cure. In this review, we will examine
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the biology of the pancreatic tumor, diagnosis, treatment techniques and clinical trials. We will likewise concentrate on the plausible role of herbal products, alone or in combination with systemic chemopreventive medications, in the treatment of the pancreatic tumor.
Biology of Pancreatic Cancer The biology of pancreatic cancer is perplexing and inadequately caught on. Pancreas has both exocrine and endocrine cells that can structure tumors; however, the likelihood is more for exocrine cells. The vast majority of the exocrine tumors are adenocarcinomas that begin in organ cells in the ductal epithelium and advances from premalignant injuries to the entirely invasive tumor. Tumors of the endocrine pancreas, commonly termed as islet cell tumors or neuroendocrine tumors, are less common and can be characterized
ACCEPTED MANUSCRIPT into gastrinomas, insulinomas, glucagonomas, somatostatinomas, VIPomas, PPomas and so forth.
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The microenvironment of the pancreatic tumor is made out of a few components, for
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example, pancreatic cancer bulk cells, pancreatic cancer stem cells (pancreatic CSCs),
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and the thick, ineffectively vascularized stroma. The studies suggest that the stroma likewise regulate the pancreatic tumor growth and development, intrusion and metastasis
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separated from its movement as the mechanical boundary. These stromal cells
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consistently interface with cancer cells by different autocrine and paracrine secretion of the pancreas, for example, platelet-derived growth factor (PDGF), transforming growth
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factor β (TGF-β) and cytokines [19]. These development variables fortify a critical
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segment of stroma called pancreatic stellate cells, which in turn express α–smoothmuscle actin and produce rich collagen fibers. These fibers add to tumor hypoxia (a
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primary stimulator of tumor movement and metastasis by influencing angiogenesis), cell survival, and apoptotic pathways [19]. Hypoxia is likewise proposed to be a major cause for drug/therapy resistance in different tumors [20, 21]. Pancreatic tumor cells apparently grow around a population of cancer stem cells (CSCs) that have the capability of self-renewal and multi-lineage differentiation [22] (Fig 1). Pancreatic CSCs can be isolated by flow cytometry utilizing CD44, CD24, and ESA as surface markers [23]. Although CD44+/CD24+/ESA+ cells constitute only 0.2-0.8% of the total cell population, they are capable of forming tumor spheres [24]. Other markers for pancreatic CSCs are CD133, CXCR4, c-Met and ALDH1 [25-28]. CXCR4 assumes an essential part in the tumor invasion and metastasis and the cells positive for both CD133 and CXCR4, show higher metastatic potential than other populations [26, 29]. In
ACCEPTED MANUSCRIPT a recent study, it has been demonstrated that human PDACs contain CSCs with high levels of CXCR4 and ABCB1, and such patients had reduced survival rate [30]. Recently
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Shankar et al. effectively demonstrated the tumorigenic potential of pancreatic CSCs
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isolated from human pancreatic tumors in NOD/SCID mice utilizing surface markers CD44, ESA, CD133, and CD24 [10]. These cells were highly tumorigenic and were
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likewise expressing ALDH and pluripotency maintaining factor, Oct-4 [10]. They further
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indicated high expression of CD133, CD24, CD44, ESA, Nanog, Notch1, MDR1 and ABCG2 in these CSCs (CD133+CD44+CD24+ESA+ cell population) contrasted with
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CD133−CD44−CD24−ESA− cell population [10].
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Various elements regulate the properties and conduct of pancreatic CSCs, for example,
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nestin can balance attack or metastasis of pancreatic CSCs, Oct-4 and Nanog can direct pancreatic CSC’s conduct and metastasis to different organs, DCLK1 can segregate
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between normal and tumoral stem cells and Sox2 controls cell proliferation and differentiation [31]. Furthermore, c-Kit and Kras likewise tweak the movement of pancreatic adenocarcinoma [32]. Epithelial to mesenchymal transition (EMT), a process of change of epithelial attributes into mesenchymal properties, is an urgent process for tumor progression and is proposed to be in charge for the appearance of cells with stem cell-like properties [33]. CSCs are thought to be the major contributory element to the absence of effective treatment for pancreatic malignancy and are in charge of tumorigenesis, metastasis, and development of chemo and radioresistance [24]. A recent study exhibited that PANC-1 cancer cell line, steadily overexpressing Oct4 and Nanog, show chemoresistance, multiplication, relocation, intrusion, and tumorigenesis in vitro and in vivo [34].
ACCEPTED MANUSCRIPT Moreover, the ALDH+CD44+CD24+ cell population is well reported to be impervious to treatment with gemcitabine [35]. Removal of CSCs is essential for robust tumor
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be a superior alternative for pancreatic cancer prevention.
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treatment, as CSCs stay untouched. Hence, drugs that can specifically target CSCs could
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Pancreatic cancer is hereditarily complex and heterogeneous in nature. Different malady conditions, for example, pancreatitis, cystic fibrosis, and inflammation have their effect
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on the initiation of pancreatic cancer and its malignant progression [36, 37]. Mutations in
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four critical genes namely Kras2, Cdkn2a, TP53 and Dpc4 (or Smad4) are frequently seen in pancreatic malignancy patients. The vast majority of the cancer patients carry one
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or more of these mutations [38]. The observed frequency of Kras mutation is more than
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90%, however, the rate of inactivation mutation of Cdkn2a, TP53, and Dpc4 are 95%, 75% and 50% respectively [39, 40]. The mutation in Kras2 brings about the consistent
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expression of irregular Ras protein that causes aberrant activation of cell proliferation and survival pathways [19]. With increasing age, the likelihood of acquiring activating mutations in Kras2 gene increases in the major organs such as lung, pancreas, colon, and other tissues. On the other hand Cdkn2a, TP53 and Dpc4 are the tumor suppressors and mutations in these genes result in their inactivation, which facilitate the proliferation and survival signaling [19, 41]. Moreover, a recent study called attention to the loss of function mutation in SWI/SNF nucleosome remodeling complex in 23% pancreatic adenocarcinomas [42]. Signaling Pathways in Pancreatic Cancer
ACCEPTED MANUSCRIPT Genetic mutations serve as the basis for abbrent signaling pathways. A comprehensive study with more than 24 pancreatic cancer cases, an average of 63 relevent genetic
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abnormalities (mainly point mutations) per tumor were classified as likely to be relevent
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in its pathogenesis [43] (reviewed in [19]). These mutations can be clubbed in 12 noteworthy signaling pathways including STAT3, Smad/TGF-β, Wnt, Notch, PI3K/Akt,
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sonic hedgehog and so forth [43] (reviewed in [19]). Aberrant signaling in these cellular
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events has been implicated in the development and progression of pancreatic tumors by
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permitting increased proliferation, angiogenesis, survival, and metastasis (Fig 2). STAT3 Pathway
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Signal transducer and activator of transcription 3 (STAT3), encoded by STAT3 gene, is
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activated in a wide variety of signaling pathways. It mediates diverse responses,
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including transmission of the signals of cytokines and growth factors from the cell membrane to the nucleus to regulate gene expression for cell development, differentiation, proliferation, survival, and angiogenesis [44-46] (Fig 3). A range of cytokines including interleukin (IL)-6, IL-9, IL-10, IL-27, tumor necrosis factor α (TNFα), and monocyte chemotactic protein-1 (MCP-1) activate the STAT3 pathway [47-49]. Various growth factors, for example, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), granulocyte colony-stimulating factor (G-CSF), and granulocytemacrophage colony-stimulating factor (GM-CSF) also activate this pathway [44-49]. Primary functions of activated STAT3 pathway incorporate cell proliferation by upregulating cyclin D1 and cyclin B1 and inhibition of apoptosis by up-regulating Bcl-2, Bcl-xL, Mcl-1. Initiated STAT3 assumes a discriminating part in tumorigenesis by
ACCEPTED MANUSCRIPT controlling angiogenesis (VEGF, FGF, and HIF1α), invasion and metastasis (MMP2, MMP9, TWIST, and ICAM1) [44-49].
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STAT3 activation has been detected in diverse type of malignancies, and its inhibition by
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use of inhibitors or short interfering RNA has prompted to reverse the malignant
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phenotype. STAT3 activation has been portrayed in almost 70% of solid and hematological malignancies [50]. Studies in conditional knockout mice have
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demonstrated that STAT3 pathway is latent in typical pancreas and is not needed for any
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vital process related to pancreatic development and homeostasis [51]. Nevertheless, it is constitutively activated in PDAC by phosphorylation of Tyr705 in human tumor
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specimens and also in various PDAC cell lines [52-55]. Further, STAT3 is necessary for
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the development of ADM process (acinar-to-ductal metaplasia), which is an early event in PDAC pathogenesis mediated by ectopic expression of the Pdx1 [54]. It is remarkable
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that Pdx1 is a transcription factior and a key regulator of early pancreatic development [54]. Another study showed that with malignant transformation, activated STAT3 promotes proliferation of cells by regulating G1/S-phase progression and supports the malignant phenotype of human pancreatic cancer [52]. IL-6 signaling dependent activation of STAT3 plays an important role in promoting PanIN progression and the PDAC development, in addition to oncogenic KrasG12D transformation [56]. The myeloid cells in the pancreas induce STAT3 activation by releasing IL-6, which promote PanIN progression and the PDAC development. Smad/TGF-β Pathway
ACCEPTED MANUSCRIPT The transforming growth factor beta (TGF-β) signaling pathway regulates various cellular processes like cell growth, cell differentiation, apoptosis and cellular homeostasis
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in both the adult organism and the developing embryo [57]. TGF-β signaling occurs from
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the membrane to the nucleus via Smad proteins [58]. Smads can be classified into 3 major groups; receptor-regulated Smads (R-Smad; Smad1, Smad2, Smad3, Smad5 and
[58]. Cascade is triggered by the binding of TGF-β
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(I-Smad; Smad6 and Smad7)
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Smad8/9), common-mediator Smad (co-Smad; Smad4) and agonistic or inhibitory Smads
superfamily ligand to a type II receptor which catalyzes the recruitment and
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phosphorylation of a type I receptor. Subsequently R-Smads are phosphorylated, linked with the coSmad and other factors, and finally accumulated in the nucleus to regulate the
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target gene expression. TGF-β receptor activation results in Smad2 and Smad3 phosphorylation, which then form heteromeric complexes with Smad4. Furthermore,
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Smad6 and Smad7, can prevent TGF-β signaling by interacting either with the receptor or with Smad2 and Smad3 [58].
TGF-β signaling pathway impairment because of inactivated Smad4 (DPC4) is often recognized in pancreatic carcinomas [59, 60]. Jonson et al., investigated a series of pancreatic carcinoma cell lines with respect to alterations of five Smad genes involved in TGF-β signaling, and demonstrated the structural rearrangement of Smad4 in 42% of these tumor cells [59]. Since, this pathway could likewise be influenced by other factors that regulate the activation of TGF-β
and its receptor genes, they further assessed
expression of uPA, uPAR, IGF2R, TGF-βR1-3, ENG, ALK1, TGF-β1-3, mutations of TGF-βR1-2, cell surface localization of TGF-βR2 and ENG, and TGF-β1 response in 14 pancreatic carcinoma cell lines [59]. The study suggested ALK5- Smad4 as a major
ACCEPTED MANUSCRIPT target for inactivation in pancreatic carcinomas and that the expression of TGF-βR2, TGF-βR3, and receptors involved in TGF-β activation are maintained [59].
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Wnt Pathway
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Wnt signaling pathway is a complex process and plays an important role in tumor
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development apart from its involvement in other physiological and pathological processes
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[61]. In canonical pathway, the ligand binding to its receptor (Frizzled/LRP receptor complexes) triggers a cascade of events that prevents β-catenin degradation inside the
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cytoplasm and permits its stabilization and translocation in nucleus where it binds to transcriptional factors of the Tcf/Lef family forming an activator complex. Abnormal
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Wnt/β-catenin signaling is reported in pancreatic cancer [62]. Activated Wnt signal leads
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to the accumulation of β-catenin in the nucleus where it activates specific target genes
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[63]. The accumulation of β-catenin is observed both in nucleus and cytoplasm in pancreatic cancer [61, 64-66]. The functional evidences are also accumulating that implicate a supporting role for β-catenin in PDAC maintenance and progression [61]. It has been also found that β-catenin accumulation and signaling could be increased through paracrine signaling taking place in the PDAC micro-environment [61]. In a recent investigation, it has been found that Wnt/β-catenin signaling inhibition by wnt-c59 results in reversal of TSA sensitivity, migration ability, and the EMT phenotype in trichostatin A-resistant Panc-1 cells (Panc-1/TSA) [67]. In spite of the fact that our understanding of the role of this pathway has increased during the last decade, the general mechanism by which β-catenin accumulation occurs in PDAC is poorly understood and needs further elucidation.
ACCEPTED MANUSCRIPT Notch Pathway Notch signaling is shown to regulate proliferation and apoptosis events in various cell
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types. The alterations in Notch signaling have various consequences including
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tumorigenesis [68, 69]. In mammals, four Notch receptors (Notch1-4) and five ligands
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(Jagged1, Jagged2, Delta-like 1(Dll-1), Dll-3, and Dll-4) have been accounted for to date [68, 70]. Binding of Notch ligand to an adjacent Notch receptor activates Notch signaling
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prompting the cleavage of Notch through a cascade of proteolytic cleavages by the
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metalloprotease, tumor necrosis factor-α-converting enzyme (TACE) and γ-secretase complexes [68, 71]. The cleavage by TACE generates Notch extracellular truncation
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(NEXT) which is subsequently cleaved by the γ-secretase complex releasing the active
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fragment Notch intracellular domain (NICD) from the plasma membrane. NICD translocates into the nucleus where it binds to members of the CSL transcription factor
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family and activates Notch target genes [68, 72]. Impaired Notch signaling is well reported in pancreatic cancers. Recently, it has been reported that inhibition of Notch signaling pathway by Notch1 siRNA or gammasecretase inhibitors, such as, MRK-003, MK-0752 etc., enhances chemosensitivity to gemcitabine in pancreatic cancer cells through activating apoptosis activity [73]. Abel et al. reported the significance of Notch pathway in maintaining cancer stem cell population in pancreatic cancer and investigated the connection of Notch pathway and percentage of the CSCs population. The inhibition of this pathway resulted in a reduced percentage of CSCs and tumor sphere formation; notwithstanding, activation demonstrated the inverse impact [74]. Further, Lee et al. suggested that the activation of the Notch pathway and the increase in CSCs might contribute to the failure of treatment in pancreatic cancer [75].
ACCEPTED MANUSCRIPT Notch has also been shown to be associated with the EMT in pancreatic cancer [72, 76]. It is remarkable that during the EMT process, epithelial cells gain the mesenchymal over
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endothelial characteristic thereby increasing in migratory and invasive capacity, leading
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to invasion and metastasis [77, 78].
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PI3K/Akt Pathway
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PI3K pathway acts via phosphorylation of FoxO proteins via Akt, which in turn impairs the DNA-binding ability and increases its affinity for 14-3-3 proteins [79]. These
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complexes are exported from the nucleus to cytoplasm leading to the inhibition of FoxOmediated survival pathways. Some other downstream effectors that regulate cell cycle
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arrest and apoptosis, such as, active FKHRL1, FKHR, and AFX are also translocated to
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the cytoplasm by similar mechanism [79]. Downstream effectors of the PI3K-Akt
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pathway are actively involved in a variety of vital and specialized functions such as differentiation and proliferation in diversified cells including adipocytes, hepatocytes, myoblasts, thymocytes and cancer cells [79]. PI3K/Akt pathway is activated in a variety of cells including fibroblastic, epithelial, and neuronal cells as survival signal. An elevated level of Akt has been reported in many types of tumors. Studies have shown the requirement of activated PI3K-Akt/FoxO signaling for the growth and survival of the pancreatic tumor. It has been found that the cells with elevated Akt levels are less sensitive to apoptosis stimuli. Akt regulates apoptosis directly by regulating its primary targets, Bad, and Caspase 9 and indirectly by controlling human telomerase reverse transcriptase subunit, FoxOs and IkappaB kinases and so forth [79].
ACCEPTED MANUSCRIPT Sonic Hedgehog Pathway Sonic hedgehog (Shh) is a member of the Hedgehog (Hh) family of secreted signaling
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proteins. Shh signaling is triggered by binding of the secreted Shh peptide to Patched
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(Ptch), which leads to inhibition of Ptch activity. Consequently, Smoothened (Smo) gets
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phosphorylated resulting in the activation of the Gli family of zinc-finger transcription factors and therefore target gene expression [80]. Shh signaling has diverse functions
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during vertebrate development and post-embryonically in tissue homeostasis [81, 82].
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Alteration in this pathway have been linked to various tumor types including pancreatic cancer [81, 82]. Activation of Shh signaling pathway has been reported to be involved in
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the regulation of the pancreatic CSC's expansion, whereas its inhibition (by impairing Gli
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binding to its promoters) has been demonstrated to upregulate DRs and Fas expression, curb Bcl-2 and PDGFRα expressions, and encourage apoptotic cell death in pancreatic
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CSCs [24]. Further, its inhibition has been shown to reduce tumor-associated stromal tissues, enhance gemcitabine uptake in tumor cells and prolong the average survival rate in pancreatic cancer mouse model [83]. Recently, Rodova et al. showed that inhibition of Shh pathway components, Gli transcriptional activity and its downstream targets by sulforaphane inhibited human pancreatic CSCs derived spheres and induced apoptosis by inhibition of Bcl-2 and activation of caspases in vitro [84]. Further, Li et al. showed that inhibition of Shh pathway by sulforaphane results in a marked reduction in EMT, metastatic, angiogenic markers with significant inhibition of tumor growth in mice. Since aberrant Shh signaling is frequently observed in pancreatic cancers, therapeutics that target Shh pathway and therefore CSCs, may improve the outcomes of patients with this devastating disease [85].
ACCEPTED MANUSCRIPT Treatment of Pancreatic Cancer: Chemotherapy and Radiotherapy The essential choice for pancreatic cancer treatment is its surgical removal. However, in
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advance metastatic stages, the treatment mainly aims to increase the survival by optimal
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control of metastases. Systemic chemotherapy may be utilized at any phase of pancreatic
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malignancy with the objective to minimize the patient’s disease-related symptoms and to prolong survival. Presently, a limited number of drugs are accessible for the treatment of
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the pancreatic tumor. Gemcitabine has been the reference regimen since 1997 when it
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was indicated better than 5-Fluorouracil (5-FU) in a phase III clinical trial [86]. A significant concern with 5-FU was the associated toxicity with its treatment, in particular,
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gastrointestinal toxicity. A combination of 5-FU and Fluoropyrimidine (S-1) could
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likewise be a decent choice as S-1 potentiates the antitumor activity of 5-FU and decreases gastrointestinal toxicity in pancreatic tumor mouse models [87]. In recent years
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different combinations, for example, the systemic treatment with Abraxane and Gemcitabine and the multidrug mix, FOLFIRINOX, have been attempted [88-109]. Despite the fact that FOLFIRINOX has been promising, it can have a remarkable reaction profile, constraining its utility in patients with poor baseline performance status [110]. Radiation therapy, combined with chemotherapy, may be used in patients whose cancers have grown beyond the pancreas and cannot be removed by surgery. Uses of radiation treatment alongside high-energy x-beams to kill cancer cells is extremely regular for the treatment of advanced stages of tumors. Pancreatic neuroendocrine tumors (NETs) usually do not respond to radiation, and therefore it is rarely used to treat these tumors. However, it can be used in case of pancreatic NETs that have spread to the bone and other tissues. Furthermore, the typical radiation treatment utilized for the treatment of the
ACCEPTED MANUSCRIPT exocrine pancreatic malignancies is External Shaft Radiation Treatment that focuses the radiation on the cancer from a machine outside the body. Radiation treatment is typically
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associated with different side effects, like skin changes in areas getting radiation, nausea
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but not the least increased risk of severe infection.
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and vomiting, diarrhea, fatigue, poor appetite, weight loss, lower blood counts and last
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Clinical Trials in Pancreatic Cancer
The chemotherapy drug, Gemcitabine, has been a standard initial treatment for patients
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with metastatic pancreatic cancer for over 15 years [86]. Various clinical trials have tried new medications, either alone or in combination with Gemcitabine (Table 1); however,
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the advancement is moderate amid the most recent decade [88-109, 111]. Gemcitabine
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alone or in combination with Capecitabine or Erlotinib remained the favored systemic
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treatment alternatives until 2010 [88-109]. Since 2010, use of FOLFIRINOX has increased both in metastatic and locally advanced cancer [110, 111]. Various drugs and combinations have been evaluated in the last couple of years, and some of them have shown promising results. Sunitinib and Everolimus have shown significant improvement in survival. Sunitinib treatment showed median progression-free survival of 11.4 months as compared with 5.5 months for patients who received the placebo. On the other hand, the patients receiving Everolimus showed median progression-free survival of 11 months as compared with 4.6 months for patients who received the placebo. Although these drugs have shown promising results, severe side effects as anemia and neutropenia were also observed.
ACCEPTED MANUSCRIPT Combination of Nab-Paclitaxel (Abraxane®), a form of the chemotherapy drug Paclitaxel bound to the human protein albumin and contained in nanoparticles, and Gemcitabine
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(Gemzar®) was also investigated in an international randomized phase III trial showing
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improved survival [112]. Patients who received the drug combination had a median overall survival of 8.5 months, compared with 6.7 months for patients treated with
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gemcitabine alone [112]. FDA approved therapy to treat patients with metastatic
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pancreatic cancer based on the results of the MPACT trial. Some other combinations, such as, gemcitabine with gamma-secretase inhibitor (MK-0752) or FG-3019 (a human
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monoclonal antibody that suppresses connective tissue growth factor), have also shown
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promising results [113].
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Herbal products, cancer prevention, and pancreatic cancer
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The relation between the consumption of certain dietary herbals and a reduced risk of cancer is becoming evident as many epidemiological and pre-clinical studies have shown the effect of herbals on health [114]. In the past few years, the cancer chemoprevention approach is directed towards polyphenols and their health-related properties and a wide range of dietary constituents show potential biological activities [114]. Studies in this line on cell/animal models and human epidemiological trials have shown the potential of dietary polyphenols as anti-carcinogenic agents. The reports have shown that phenolic compounds have the capability to inhibit the molecular events in the cancer initiation, promotion, and progression stages. They may increase the expression of pro-apoptotic components in initiated proliferating cells and thereby prevent or delay tumor development. Although it seems that phenolic compounds induce apoptosis in a precise manner in cancer cells but in some human studies no promising results were obtained. A
ACCEPTED MANUSCRIPT Cohort Study of Diet and Cancer in Netherlands suggested no effect of the consumption of black tea on the risk for colorectal, stomach, lung and breast cancers [115]. A similar
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study was performed in Japan involving more than 25,000 stomach cancer patients with a
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similar observation i.e. no association of consumption of green tea with gastric cancer risk [116]. Some other studies on different types of cancer also indicated the same
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conclusion [117-119]. On the contrary, a decreased risk for the different types of cancer
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these phenolic compounds [118-122].
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has been reported after the consumption of flavonoids or certain foods or drinks rich in
The use of herbals in the treatment of pancreatic cancer is a novel approach and is
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continuously gaining the attention of investigators. Previous research in this area was
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focused on inducing apoptosis but recently these herbals have been used in the targeting of other key pathways of cell survival, angiogenesis, metastasis, and differentiation. Easy
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availability and less or no toxicity even at higher doses have made them the preferable choice over other cancer chemopreventive options (Fig. 2). Resveratrol
Resveratrol, a phytoalexin, is commonly found as an ingredient in red wine, skins of grapes, peanuts and so forth. It possess anti-tumorigenic, anti-inflammatory, and antioxidant properties [123]. Its preventive role against cancers, cardiovascular diseases, and various neurological disorders has been widely reported [124-126]. Hydroxylation of resveratrol by CYP1B1 generates two major metabolites namely piceatannol and 3,4,5,4’-tetrahydroxystilbene that substantially contribute to its chemopreventive activities by inhibiting tyrosine kinase and inducing apoptosis [127-129].
ACCEPTED MANUSCRIPT Chemopreventive effects of resveratrol against various cancers have been extensively investigated in both in vitro and in vivo. It has been shown to have anti-tumor activity by
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inhibiting angiogenesis, endothelial cell migration, tumor formation and by blockage of
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oxygen free radical formation [130-132] (Table 2). Due to its lipophilic nature, it readily crosses the plasma membrane and establishes dynamic homeostasis by inhibiting the
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phase I (mainly CYP450s) and inducing phase II enzymes (UDP-glucuronosyl
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transferase, NAD(P)H quinone oxidoreductase, and glutathione-s-transferases) during stress conditions [133-138]. In cancerous cells, it inhibits the expression of inducible
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nitric oxide (NO) synthase and NO production [139]. It also inhibits the formation of a preneoplastic lesion in mouse mammary glands and proliferation of a variety of cancer
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cells in culture including, human colon, breast, and prostate cancer cells [140-143]. Resveratrol sensitizes a broad spectrum of tumors including lung carcinoma, acute
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myeloid leukemia, promyelocytic leukemia, multiple myeloma, prostate cancer, oral epidermoid carcinoma, and pancreatic cancer.
Zhou et al. showed that it enhances
caspase-3 activation and p53 and p21 expression in capan-2 and colo357 pancreatic cancer cell lines [144]. A recent approach, using human pancreatic CSCs (CD133+CD44+CD24+ESA+), showed that resveratrol sensitizes and inhibits the growth and development of pancreatic cancer lesion in KrasG12D mice [10]. This study further showed that the resveratrol inhibits pluripotency maintaining factors (Nanog, Sox-2, cMyc and Oct-4), drug resistance gene ABCG2, CSC's migration, invasion, self-renewal, and components of EMT (Zeb-1, Slug, and Snail) [10]. Resveratrol inhibits cell growth, proliferation and expression of the anti-apoptotic proteins Bcl-2, Bcl-xL, and XIAP and induces apoptosis, cell cycle arrests, caspases and pro-apoptotic gene Bax in pancreatic
ACCEPTED MANUSCRIPT cancer cell lines [145]. Additionally, resveratrol has been found to suppress proliferation and anchorage-independent growth of pancreatic cancer by inhibiting leukotriene B4
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(LTB4) production and expression of the LTB4 receptor 1 (LTB4R1) [146]. It is
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remarkable that LTB4 is a hydrolysis product of the leukotriene A4 (LTA4), and the process is catalyzed by LTA4 hydrolase, a known target for prevention and therapy of
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cancers including PC [147]. Resveratrol can directly bind to leukotriene A4 hydrolase
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(LTA-4H) and inhibit its activity and, therefore, LTB4 production [146].
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Curcumin
Curcumin is one of the most commonly used and highly investigated phytochemical.
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During the last decade, our understanding of its therapeutic potential and the multiple
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mechanisms by which it offers chemoprevention against various cancers has been
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increased [148] (Table 3). The various pharmacological effects of curcumin include apoptotic, anti-proliferative, anti-oxidant, and anti-angiogenic properties. The previous studies have highlighted that curcumin targets multiple signal transduction pathways and that it suppresses a number of essential elements in cellular signaling pathways, for example, phosphorylation catalyzed by protein kinases, c-Jun-activated protein 1 (AP-1) activation and prostaglandin biosynthesis. It has also been found that curcumin potentiates radiotherapy in PC cure probably by involving selective regulation of radiotherapy-induced NF-κB [149]. Studies have shown that curcumin inhibits cell proliferation and induces apoptotic cell death mediated by PARP cleavage and Caspase-3 in MIAPaCa-2, Panc-1 and BxPC-3 pancreatic cancer cells [150]. Subramaniam et al. showed a significant reduction in tumor volume and
ACCEPTED MANUSCRIPT angiogenesis in curcumin treated tumor xenografts [151]. They further showed that curcumin inhibits cell proliferation, induces of G2-M arrest and apoptosis, enhances
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phosphorylation of checkpoint kinase 2 (Chk2) coupled with higher levels of nuclear
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cyclin B1 and Cdc-2, and increases expression of cyclooxygenase-2 (COX-2) [151]. Curcumin also inhibits ERK activity and suppresses EGFR and Notch-1 signaling leading
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to increased apoptosis in pancreatic cancer. Glienke et al. showed that incubation with
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curcumin results in down-regulation of Wilms' tumor gene 1 (WT1; a gene frequently expressed in pancreatic cancer) in a dose-dependent manner [152]. Additionally,
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curcumin has been shown to restrain STAT3 and induce apoptosis by inhibiting the
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expression of the anti-apoptotic gene Survivin/BIRC4 in pancreatic cancer cells [153].
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Recently Bar-Sela et al. reviewed the accomplished and continuing clinical trials with curcumin as an anticancer agent [154]. In one trial, 17 patients were treated with the oral
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dose of 8 gm/day of curcumin in combination with Gemcitabine. Although the results showed that this combined treatment is tolerable in patients; nevertheless, it has been suggested to reduce the dose of curcumin [155]. Dhillon et al. used only curcumin as the 1st line treatment for the 25 patients. They found that curcumin down regulates the expression of NFκB, COX-2, and the phosphorylation of STAT3 in peripheral blood [156]. In spite of these encouraging results, extensive clinical trials are needed before drawing any conclusion. Epigallocatechin gallate (EGCG) Epigallocatechin gallate (EGCG) is a most extensively studied catechin and the major polyphenol present in green tea. Various studies have shown that EGCG offers protection
ACCEPTED MANUSCRIPT against pancreatic cancer among the other tumors (Table 4); however, the exact molecular mechanism by which EGCG suppresses human pancreatic cancer cell
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proliferation is unclear. Kürbitz et al. showed anticancer properties of EGCG on human
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pancreatic ductal adenocarcinoma (PDAC) cells PancTu-I, Panc1, Panc89 and BxPC3 in vitro [157]. They found that EGCG inhibits proliferation of PDAC cells in a dose- and
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time-dependent manner. The protein expression analysis performed with PancTu-I cells
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evidently showed EGCG-mediated modulation of cell cycle regulatory proteins (cyclins, cyclin-dependent kinases, and inhibitors). The study further stated that EGCG inhibits
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TNFα-induced activation of NF-κB and consequently secretion of pro-inflammatory and invasion-promoting proteins like IL-8 and uPA [157]. Moreover, previous studies have
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demonstrated that EGCG decreases cell adhesion ability on micro-pattern dots, accompanied by dephosphorylation of both focal adhesion kinase and insulin-like growth
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factor-1 receptor (IGF-1R) in AsPC-1 and BxPC-3 cells [158] [159] [64]. EGCG has been also found to aid retained activation of MAPK signaling, suppressed growth, reduced cell viability, and increased apoptosis in these cells in a dose-dependent manner [158].
Effects of EGCG on heat shock proteins were also investigated. A study by Li Y et al. showed that the binding of EGCG to Hsp90 impairs the association of Hsp90 with its cochaperones, thereby inducing degradation of Hsp90 client proteins (Akt, Cdk4, Raf-1, Her-2, and pERK) consequently anti-proliferating effects in pancreatic cancer cells [160]. Basu and Haldar showed that EGCG causes the disappearance of intact 21 kDa Bid protein and induces activation of caspase-8 leading to cell death in MIA PaCa-2 cells [161]. Further, involvement of transmembrane extrinsic signaling in this polyphenol
ACCEPTED MANUSCRIPT triggered pancreatic carcinoma cell death was confirmed by RNase protection assay that clearly showed up-regulation of the members of death receptor family [161] [160].
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Shankar et al. examined the role of EGCG in inhibiting growth, invasion, metastasis and
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angiogenesis of human pancreatic cancer cells in a xenograft model system [162]. They
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found that EGCG inhibits viability, capillary tube formation, and migration of HUVEC. Additionally, they observed EGCG-mediated inhibition of proliferation (Ki-67 and
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PCNA staining), angiogenesis (vWF, VEGF and CD31) and metastasis (MMP-2, MMP-
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7, MMP-9 and MMP-12), and induction of apoptosis (TUNEL), caspase-3 activity and growth arrest (p21/WAF1) in vivo [162]. They also found a significant reduction in the
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circulating vascular endothelial growth factor receptor 2 (VEGF-R2) positive endothelial
Genistein
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treatment [162].
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cells, ERK activity, and induction of p38 and JNK activities in vivo following EGCG
Genistein is found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea, in the medicinal plant, Flemingia vestita, and coffee [159, 160, 163-165]. It has multiple effects in living cells, such as activation of PPARs, estrogen receptor-β, Nrf2 anti-oxidative response, stimulation of autophagy and inhibition of several tyrosine kinases, topoisomerase, and mammalian hexose transporter GLUT-1 [73, 166-174]. Genistein also affects tumor formation, cell multiplication and differentiation, angiogenesis, and signaling triggered by growth factors [175-184]. The most critical activity that contributes to the chemopreventive potential of genistein is tyrosine kinase inhibition, mostly of epidermal growth factor receptor EGFR. Additionally, the inhibitory
ACCEPTED MANUSCRIPT effect of genistein on DNA topoisomerase II is also a major contributor to its cytotoxic activity [170, 172].
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Genistein inhibits cell growth, clonogenicity, cell migration and invasion, EMT
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phenotype, and formation of pancreatospheres consistent with reduced expression of
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CD44 and EpCAM [185]. Wang et al., showed that genistein restricts pancreatic cancer cell invasion by inhibiting cell growth and inducing apoptosis along with attenuation of
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FoxM1 and its downstream genes (survivin, Cdc25a, MMP-9, and VEGF) [186].
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Sulforaphane
Sulforaphane has been reported to inhibit the growth of established tumors and prevent
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chemically induced cancers in animal models [187-189] (Table 5). It has been shown to inhibit Akt pathway in ovarian, prostate and colorectal cancers [189-191] and down-
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regulate β-catenin in HeLa and HepG2 cells [192]. Additionally, it also targets breast cancer stem/progenitor cells effectively in both in vitro and in vivo conditions [193]. The studies have shown that recipient NOD/SCID mice inoculated with tumor cells derived from sulforaphane-treated primary xenograft failed to develop tumor growth, whereas control tumor cells quickly generate large tumors [194]. Furthermore, sulforaphane has also been shown to inhibit the self-renewal capacity of pancreatic CSCs. Srivastava et al., showed that inhibition of Nanog enhances the inhibitory effects of sulforaphane on the self-renewal capacity of CSCs [195]. Sulforaphane induces apoptosis by activating caspase-3 and inhibiting the expression of Bcl-2 and XIAP, as well as phosphorylation of FKHR. Additionally, sulforaphane is suggested to block signaling involved in early metastasis by inhibiting the expression of
ACCEPTED MANUSCRIPT proteins involved in the epithelial-mesenchymal transition (beta-catenin, vimentin, TWIST1, and ZEB1) [195]. Additionally, sulforaphane, in combination of with TRAIL,
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has been suggested to be a promising strategy for targeting pancreatic tumor initiating
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cells (TICs). It has been found that it could abrogate the resistance of pancreatic TICs to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by interfering with
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Garlic
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TRAIL-activated NF-κB signaling [196].
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Garlic has been traditionally used for varied human ailments around the world. Epidemiological observations and preclinical studies, both in cell and animal models,
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suggest the anti-carcinogenic potential of garlic and its constituents [197]. Chemical
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analysis revealed that the protective effects of garlic are due to the presence of
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organosulfur compounds mainly allyl derivatives [197]. Additionally, it modulates the activity of several metabolizing enzymes involved in the activation and detoxification of carcinogens and inhibits DNA adduct formation. It possess anti-oxidative and free radicals scavenging properties and regulates cell proliferation, apoptosis, and immune responses. Recent data suggest that garlic also modulates cell-signaling pathways to avoid proliferation of unwanted cells thereby imparting strong cancer chemopreventive, as well as cancer therapeutic effects [197]. Benzyl Isothiocyanate (BITC) Due to their capability to induce apoptosis, modulate signaling pathways and inhibit angiogenesis, isothiocyanates (ITCs) have shown a great promise as chemopreventive agents against various tumors in recent years [198]. Benzyl isothiocyanate (BITC) is a
ACCEPTED MANUSCRIPT major ITC compound present in cruciferous vegetables. BITC suppresses the initiation and progression of a variety of cancers including lung, esophageal, forestomach, urinary
PT
bladder, mammary, liver, colon, and pancreatic tumors [198-203]. Various preclinical
RI
and mechanistic studies have supported the anticancer efficacy of BITC, and it has been found to suppress the growth of human pancreatic cancer cells both in vitro and in vivo.
SC
BITC is reported to induce G(2)/M phase cell cycle arrest, and apoptotic cell death in
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pancreatic cancer cell/animal models [204-207]. The apoptotic potential of BITC is attributed to its capability to activate MAPK family members i.e. ERK, JNK and P38 by
MA
catalyzing their phosphorylation at Thr202/Tyr204, Thr183/Tyr185, and Thr180/Tyr182 respectively in a dose-dependent manner [206]. Additionally, the potential to inhibit the
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D
phosphorylation and expression of NF-kB most likely via inhibition of HDAC1/HDAC3, is suggested to be another contributory factor to the apoptotic potential of BITC [204].
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Furthermore, it has been found to inhibit angiogenesis and metastasis by suppressing VEGF and MMP-2 expression in pancreatic cancer cells [208]. Recently Boreddy et al., showed that BITC offers protection against pancreatic tumor growth by effectively containing STAT-3 and HIF-1α and VEGF expression in BxPC-3 and PanC-1 pancreatic cancer cells [208]. It reduces the phosphorylation of PI3K, Akt, Pdk1, mTOR, FoxO1, and FoxO3a and increases apoptosis in tumor xenograft mouse model. BITC treatment also decreases the binding of FoxO1 with 14-3-3 protein suggesting it’s nuclear retention and subsequent elevation of FoxO-responsive proteins involved in apoptosis (Bim) and cell cycle arrest (p27 and p21) [209]. BITC has also been shown to sensitize pancreatic tumors for radiotherapy. BITC treatment in a combination of X-rays or gamma-irradiation reduces cell survival as
ACCEPTED MANUSCRIPT compared with individual (X-rays or gamma-irradiation) exposure in pancreatic cancer cells. This effect is suggested to be due to the inhibition of cell proliferation and anti-
PT
apoptotic genes like XIAP/IAP, and augmentation of apoptosis protease activating factor-
RI
1 (Apaf-1) triggered by BITC [208]. It is remarkable that Apaf-1 is essential for activation of caspase-9 in stress-induced apoptosis [208].
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Piperlongumine:
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Piperlongumine (PL) is an alkaloid found in the fruits of long pepper plants that displays
MA
potent growth-inhibitory properties in a variety of cancer cell lines and various animal models. It has been identified to target cancer cells selectively over normal cells through
D
an ROS-dependent mechanism in a cell-based small-molecule screening and quantitative
TE
proteomics approach [210]. It increases ROS levels and cancer-selective cell death by directly binding and inhibiting the antioxidant enzyme glutathione S-transferase pi 1
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(GSTP1) [210, 211]. Raj et al., have shown that PL selectively targets pancreatic cancer cells, PANC-1, and MIA PaCa-2- both of which harbor mutated K-ras [210]. A recent study by Dhillon et al. further supported this finding and suggested that PL also targets BxPC-3 pancreatic cancer cells that contain wild-type K-ras [212]. They further showed the anti-cancer effects of PL in vivo. PL reduces tumor volume, increases oxidative DNA damage (8-OHdGhigh), and reduces proliferation (Ki-67low) in nude mice xenografts for PANC-1 [212]. Conclusion and future perspectives Pancreatic cancer is continuously posing a challenge to the clinicians and researchers. We are still relying on the old traditional therapies. The major drawback of current therapy is
ACCEPTED MANUSCRIPT their unilateral actions on one or two pathways whereas the approach should be to target several targets simultaneously. The combination therapy is a right approach in this
PT
direction, but associated side effects are a major concern. Since the small population of
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pancreatic CSCs is mostly responsible for the pathogenesis of pancreatic cancer, an efficient, targeted therapy for pancreatic CSCs is also an excellent approach. However,
SC
the problem is the resistance of pancreatic CSCs against conventional treatment but still
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developmental pathways such as the hedgehog, Wnt, Notch, etc. can be targeted.
MA
Flavonoids have emerged as potential chemopreventive candidates for cancer treatment, especially by their ability to induce apoptosis. These can interfere with the initiation,
D
development and progression of cancer by the modulation of cellular proliferation,
TE
differentiation, apoptosis, angiogenesis, and metastasis. Flavonoids have been shown to target cancer cells specifically with no or insignificant effects on healthy cells in vitro.
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Nevertheless, some studies suggest to include experimental conditions (dose, cell type, culture conditions and treatment length) while interpreting the results of in vitro studies because the biological outcome can be affected. Since the apparent phenomenon is a result of complex interaction of different cellular events, the mechanisms for inducing the apoptosis of these polyphenols may overlap with other signaling cascades. Therefore, the promising strategy could be the promotion of programmed cell death through the modulation of different proteins in other pathways that can contribute to cell death. Flavonoids exhibit some characteristic effects, for example, induction of apoptosis, activation of caspases, down-regulation or up-regulation of Bcl-2 family members, induction of cell cycle arrest and inhibition of survival/proliferation signals. Moreover, the effects of these plant products on pancreatic cancer initiation, promotion and
ACCEPTED MANUSCRIPT metastasis has also discussed in the light of available literature. The results from in vitro experiments constitute a valuable tool for elucidating the pathways involved in the
PT
overall carcinogenesis process, although these cannot be directly extrapolated to clinical
RI
effects. The best thing about herbal products is that they target multiple signaling events simultaneously; however; more studies are needed to understand clearly the mechanisms
SC
of action of flavonoids as modulators of cell survival and apoptosis.
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Acknowledgments
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We acknowledge our lab members for critical reading of the manuscript, insightful discussions, and valuable advice. The project was funded by the National Institutes of
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Health (RKS) and The VA Merit Award (SS).
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Table 1: List of some of the completed clinical trials on pancreatic cancer (Source: www. ClinicalTrials.gov) Rank
Interventions
NCT Number
1 2
Drug: RAD001 Drug: Gemcitabine|Drug: Albuminbound paclitaxel Drug: gemcitabine hydrochloride|Drug: imatinib mesylate Dietary Supplement: genistein|Drug: erlotinib hydrochloride|Drug: gemcitabine hydrochloride Drug: Ixabepilone|Drug: Cetuximab Biological: cetuximab|Drug: docetaxel|Drug: irinotecan hydrochloride Drug: alvocidib|Drug: docetaxel
Drug: bortezomib|Drug: carboplatin|Other: laboratory
3
4
5 6
7
8
Conditions
NCT00409292 NCT00398086
Enroll ment 33 67
NCT00161213
44
Pancreatic Cancer
NCT00376948
20
Pancreatic Cancer
NCT00383149 NCT00042939
58 94
Metastatic Pancreatic Cancer Pancreatic Cancer
NCT00331682
10
NCT00416793
9
Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Acinar Cell Adenocarcinoma of the Pancreas|Duct Cell
Pancreatic Cancer Metastatic Pancreatic Cancer
ACCEPTED MANUSCRIPT
Drug: bevacizumab [Avastin] Drug: Erlotinib, escalating dose|Drug: Erlotinib, standard dose|Drug: Gemcitabine
NCT01214720 NCT00652366
607 467
12
Drug: Ipilimumab|Biological: Pancreatic Cancer Vaccine Biological: cixutumumab|Drug: erlotinib hydrochloride|Drug: gemcitabine hydrochloride Drug: Gemcitabine|Drug: Erlotinib|Drug: Sorafenib Biological: bevacizumab|Drug: erlotinib hydrochloride|Other: laboratory biomarker analysis Drug: Capecitabine|Drug: Docetaxel Drug: Abraxane Drug: gamma-secretase/Notch signaling pathway inhibitor RO4929097
NCT00836407
30
NCT00617708
134
19 20
21 22 23
24
25
26 27 28
29
SC
Pancreatic Cancer
NCT00365144
36
Pancreatic Cancer
NCT00290693 NCT00691054 NCT01232829
45 20 18
NU
45
Drug: Lenalidomide|Drug: Gemcitabine Drug: sorafenib tosylate|Drug: gemcitabine hydrochloride|Other: laboratory biomarker analysis Drug: GSK1120212|Drug: Gemcitabine|Drug: Placebo Drug: Gemcitabine|Drug: AG013736|Drug: Gemcitabine Drug: dasatinib|Procedure: laboratory biomarker analysis|Procedure: physiologic testing Drug: gemcitabine|Drug: placebo|Drug: Erlotinib|Drug: apricoxib Drug: AG-013736|Drug: Gemcitabine|Drug: Gemcitabine|Drug: placebo Drug: Albumin-bound paclitaxel|Drug: Gemcitabine Drug: cohort 1|Drug: cohort 2|Drug: cohort 3|Drug: cohort 4 Drug: gemcitabine hydrochloride|Drug: tanespimycin
NCT00837031
72
Pancreatic Cancer Pancreatic Cancer Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Metastatic Pancreatic Cancer
NCT00114244
52
Stage IV Pancreatic Cancer
NCT01231581
160
Cancer
NCT00219557
111
Pancreatic Neoplasms
NCT00474812
49
NCT00709826
109
Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Pancreatic Cancer|Metastatic Pancreatic Cancer
NCT00471146
630
Carcinoma, Pancreatic Ductal
NCT00844649
861
Metastatic Pancreatic Cancer
NCT00439179
27
Metastatic Pancreatic Cancer
NCT00577889
21
Drug: PCI-27483|Drug: Gemcitabine
NCT01020006
42
Adenocarcinoma of the Pancreas|Recurrent Pancreatic Cancer|Stage IV Pancreatic Cancer Pancreatic Cancer|Ductal Adrenocarcinoma|Exocrine Pancreatic Cancer
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16 17 18
Stage IV Pancreatic Cancer
NCT00696696
D
15
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14
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13
Pancreatic Cancer
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9 10
Adenocarcinoma of the Pancreas|Stage IV Pancreatic Cancer Pancreatic Cancer Pancreatic Cancer
PT
biomarker analysis
ACCEPTED MANUSCRIPT
37
38 39
41
42 43 44 45
Drug: Cetuximab|Drug: Gemcitabine|Drug: Oxaliplatin|Drug: Capecitabine|Radiation: Radiotherapy Drug: Gemcitabine
NCT00338039
69
Metastatic Pancreatic Adenocarcinoma Pancreatic Cancer
NCT00390182
38
Biological: DTA-H19 Drug: Fentanyl sublingual spray|Drug: Placebo Drug: Avastin|Drug: Tarceva|Radiation: Radiation Therapy Drug: Gemcitabine|Drug: Sunitinib
NCT00711997 NCT00538850
9 130
Gastrointestinal Neoplasms|Ovarian Neoplasms Pancreatic Neoplasms Cancer
NCT00735306
12
Pancreatic Cancer
NCT00556049
72
RI
PT
367
SC
36
NCT01124786
NU
34 35
Pancreatic Neoplasms
NCT00661830
103
Renal Cell Carcinoma|Neoplasm Metastases Adenocarcinoma
NCT00448136
83
Neoplasms
Drug: Avastin (Bevacizumab, RHUMAB VEGF)|Drug: Capecitabine|Radiation: Radiation Therapy Drug: Sunitinib
NCT00113230
25
Rectal Cancer
NCT01121562
12
Drug: RAD001|Drug: Octreotide Depot Drug: Sunitinib malate|Procedure: Hepatic Artery Embolizations Other: Cocoa Polyphenols
NCT00113360
67
NCT00434109
39
NCT01617603
62
Pancreatic Neuroendocrine Tumors Neuroendocrine Carcinoma|Islet Cell Carcinoma Neuroendocrine Tumor|Islet Cell Tumor Diabetes Type 2
Drug: Gemcitabine|Drug: Placebo|Drug: Sorafenib Drug: bevacizumab [Avastin]|Drug: 5 FU|Drug: Streptozotocin|Drug: Xeloda
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33
142
D
32
NCT00637247
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31
Drug: imexon in combination with gemcitabine|Drug: imexon placebo + gemcitabine Drug: CO-1.01|Drug: Gemcitabine
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30
ACCEPTED MANUSCRIPT Table 2: Summary of recent findings showing chemopreventive potential of resveratrol against pancreatic cancer Effect
Reference
MIA PaCa-2 cells
Inhibits proliferation and induces apoptosis
Panc-28 and Hs766T
Increases calcium levels and prevents migration of TG2-
cells
expressing cells
Capan-2 cells
Inhibits tumor growth, induced apoptosis, and up-regulated Bax
[213]
[214]
MA
NU
SC
RI
PT
Cells
[215]
Inhibits cell proliferation, migration, and induces expression of
TE
BxPC-3 and Panc-1
D
and VEGF-B expression
[216]
EMT-related genes (E-cadherin, N-cadherin, vimentin, MMP-2,
PANC-1,
AC CE P
and MMP-9)
CFPAC-1,
Inhibits viability and miR-21 expression and increases Bcl2
[217]
and MIA Paca-2 cells
expression
BxPC-3 and Panc-1
Inhibits the growth Gli1, Ptc1, CCND1, and BCL-2
[218]
PANC-1, MIA PaCa-
Up-regulates p21/CIP1, p27/KIP1, Bim, activates csapase-3,
[219]
2, Hs766T, and AsPC-
reduces phosphorylation of ERK, PI3K, Akt, FoxO1, and
1
FoxO3a
ACCEPTED MANUSCRIPT Table 3: Summary of recent findings showing chemopreventive potential of curcumin against pancreatic cancer Effect
MIA PaCa-2
Inhibits the proliferation and enhances apoptosis in MIA PaCa-2 (tumor
xenograft model)
RI
mouse
[220]
cells and inhibits tumor growth and the expression of the transcription nuclear factor NF-κB and NF-κB-regulated gene
SC
and
Reference
PT
Cells/ animals
the
NU
products in xenograft mouse model MiaPaCa-2 and Panc-1
Down-regulates
expression
of
miR-221
resulting
in
cells
upregulation of PTEN, p27(kip1), p57(kip2), and PUMA leading
[221]
and
Inhibits cell proliferation, reduces tumor growth and angiogenesis
mouse
(tumor
xenograft model)
[222]
as determined by a reduced number of blood vessels and
D
MIA PaCa-2
MA
to the inhibition of cell proliferation and migration
decreased expression of vascular endothelial growth factor and
TE
annexin A2 proteins
Activates TNFR, CASP 8, CASP3, BID, BAX, and down-
2
regulates NFκB, NDRG 1, and BCL2L10 gene
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BxPC-3 and MiaPaCa-
TGF-β1-stimulated
[223]
Inhibits proliferation, induces apoptosis and reverses the EMT
[224]
AsPC-1 and MiaPaCa-
Decreases
[225]
2
formation of pancreatospheres, invasive cell migration, and CSC
PANC-1 cells
pancreatic
cancer
cell
survival,
clonogenicity,
function AsPC-1,
MiaPaCa-2,
Panc-1, human
and
mouse cancer cells
Inhibits tumor growth through mitotic catastrophe by increasing
BxPC-3
the expression of RNA binding protein CUGBP2, thereby
Pan02
inhibiting the translation of COX-2 and VEGF expression
pancreatic
[151]
ACCEPTED MANUSCRIPT Table 4: Summary of recent findings showing chemopreventive potential of EGCG against pancreatic cancer Reference
PANC-1
Suppresses
proliferation
and
PT
Effect
induces
apoptosis,
RI
Cells/ animals
[226]
modulates the PI3K/Akt/mTOR signaling pathway Regulates RKIP/ERK/NF-κB and/or RKIP/NF-κB/Snail
SC
AsPC-1 cells
[227]
and inhibits invasive metastasis c
nude
mice
(tumor
xenograft model)
Inhibits pancreatic cancer orthotopic tumor growth,
NU
Balb
[162]
angiogenesis, and metastasis, inhibits PI3K/Akt and ERK
Colo357
human
pancreatic
adenocarcinoma cells
MA
pathways and activation of FKHRL1/FoxO3a With PGHS-2-specific inhibitor celecoxib, synergistically
[228]
diminishes metabolic activity via apoptosis induction and release
of
pro-angiogenic
vascular
D
down-regulates
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endothelial growth factor (VEGF) and invasiveness-
PANC-1
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promoting matrix metalloproteinase (MMP)-2
Inhibits HIF-1α protein expression, P-gp mRNA and
[229]
protein levels and cell proliferation
AsPC-1 and PANC-1
Suppresses the growth, invasion, and migration, induces
[230]
apoptosis by interfering with the STAT3 signaling pathway and enhances the therapeutic potential of gemcitabine and CP690550
Human pancreatic cancer stem
Inhibits Nanog, c-Myc and Oct-4 expression, self-
cells
renewal, proliferation, EMT, components of Shh pathway
(CD133+/CD44+/CD24+/ESA+)
(smoothened, patched, Gli1 and Gli2) and Gli transcriptional activity, and induces apoptosis by inhibiting Bcl-2 and XIAP and activating caspase-3
[231]
ACCEPTED MANUSCRIPT Table 5: Summary of recent findings showing chemopreventive potential of sulforaphane against pancreatic cancer Effect
Established BxPc-3 and AsPC-1
Increases Cx43 and E-cadherin levels, inhibits c-Met and
PDA cell lines and immortalized
CD133, improved the functional morphology and
CRL-4023
communication of gap junctions.
human PDA cells
Inhibits cell viability and NF-κB DNA binding activity,
[233]
NU
MIA PaCa-2 and Panc-1
[232]
RI
SC
hTERT-HPNE
Reference
PT
Cells/ animals
induces cell apoptosis by activation of caspase-3 and PARP cleavage, increases pERK1/2, c-Jun, p38 MAPK,
MA
p53 protein expression when used in combination with aspirin and curcumin NOD/SCID/IL2Rgamma
mice
components,
D
(tumor xenograft model)
Inhibits growth of tumors, expression of Shh pathway EMT,
pluripotency
[85]
maintaining
TE
transcription factors, angiogenic markers and induces apoptosis Inhibits CSC’s derived spheres, components of Shh
cells
human
pathway and Gli transcriptional activity, expression of
pancreatic cancer stem cells
pluripotency maintaining factors (Nanog and Oct-4) as
(CD133+/CD44+/CD24+/ESA+)
well as PDGFRα and Cyclin D1
Pancreatic
Disrupts protein-protein interaction in Hsp90 complex for
AC CE P
Human normal pancreatic stem (HPSC)
and
cancer
mouse model
xenograft
[84]
[234]
its chemopreventive activity
MIA-PaCa2
Potentiates the inhibitory effects of gemcitabine and 5-
[235]
flurouracil on clonogenicity, spheroid formation, ALDH1 activity, Notch-1 and c-Rel expression
PANC-1, AsPC-1
MIA
PaCa-2
and
Inhibits cell proliferation, colony formation, phosphorylation of Akt and ERK, activates FoxO transcription factors and induces apoptosis
[79]
ACCEPTED MANUSCRIPT References
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT
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ACCEPTED MANUSCRIPT Disclosure of Potential Conflicts of Interest
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The authors have declared that no Conflicts of Interest exist.
ACCEPTED MANUSCRIPT Highlights
Pancreatic cancer (PC) is a complex hereditary disease with high mortality
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rate.
PC exhibits resistance against chemo- and radiotherapy.
PC stem cells contribute greatly to its resistance against chemo- and
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Herbal products target multiple pathways involved in carcinogenesis
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radiotherapy.
simultaneously.
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cure.
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Solution involving herbals may be a smart thought for better results in PC
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