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Review
Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview Li-Juan Xiu, Da-Zhi Sun, Jian-Peng Jiao, Bing Yan, Zhi-Feng Qin, Xuan Liu, Pin-Kang Wei n, Xiao-Qiang Yue n Department of Traditional Chinese Medicine, Shanghai Changzheng Hospital, Shanghai 200003, China
art ic l e i nf o
a b s t r a c t
Article history: Received 12 December 2014 Received in revised form 10 May 2015 Accepted 10 May 2015
Ethonopharmacological relevance: Cancer is considered to be the second leading cause of human death. It is unsatisfactory that in the past decades, the treatment for cancer has not progressed as fast as it was expected, as only 50% of newly diagnosed patients could be cured even today. The development of cancer is a multifactorial process, involving tumor cells themselves, the interactions between tumor cells and their microenvironments, as well as the interactions between tumor cells and the host's immunity. Focusing on any single goal may bring limited benefits. Aim and methods of the study: Phlegm-eliminating herbs, which can reduce phlegm and eliminate pathological metabolites, are commonly used to treat cancer in China. However, the underlying molecular targets and efficacy of herbal medicines in cancer treatment still remain unclear. In this study, we reviewed the potential anticancer mechanisms of some phlegm-eliminating herbs and their active ingredients from the articles through such scientific databases as MEDLINE, PubMed, and Google Scholar. Results: We found that the anticancer mechanisms of phlegm-eliminating herbs and ingredients include inducing apoptosis, anti-proliferation, preventing tumor invasion and metastasis, and reducing resistance to chemotherapy. In addition, some phlegm-eliminating herbs and their ingredients have antiinflammatory and anti-metabolic syndrome effects. Conclusions: We suggest that the phlegm-eliminating herbs and ingredients are potential candidates for anticancer treatment and cancer prevention by playing a comprehensive role. & 2015 Published by Elsevier Ireland Ltd.
Chemical compounds studied in this article: 3',4',3,5,6,7,8-heptamethoxyflavone (PubChem CID: 150893) deapioplatycodin D (PubChem CID: 86578026) glycoprotein (PubChem CID: 439212) hesperidin (PubChem CID: 10621) limonin (PubChem CID: 179651) nobiletin (PubChem CID: 72344) platycodin D (PubChem CID: 162859) tangeretin (PubChem CID: 68077) verticinone (PubChem CID: 167691) Keywords: Cancer Phlegm Traditional Chinese medicine Herb
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticancer activities of phlegm-eliminating herbs in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Apoptosis-inducing and anti-proliferative effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Prevention of tumor invasion and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Synergies with chemotherapy and reduced resistance to chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antitumor activities of phlegm-eliminating herbs in vivo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: AMPK, AMP-activated protein kinase; ACC, acetyl-CoAcarboxylase; COX, cyclooxygenase; CDK, cyclin-dependent kinase; CaMK, Ca2 þ /calmodulindependent protein kinase; CPT, Cholinephosphotransferase; Egr, early growth response gene; ERK, extracellular signal-related kinase; GSH-Px, Glutathione peroxidase; HDL-C, High Density Lipoprotein Cholesterol; hTERT, human telomerase reverse transcriptase; HPV, human papillomavirus; iNOS, inducible nitric oxide synthase; IL, interleukin; JNK, c-Jun N-terminal kinase; K-ras, Kirsten RAS; LDL-C, low density lipoprotein-cholesterol; MAPK, mitogen-activated protein kinases; MCP, Membrane cofactor protein; MDA, malondialdehyde, multidrug resistance; MMP, matrix metalloproteinase; NO, nitrie oxide; NF-κB, nuclear factor-kappaB; NK, nature killer cell; PARP, poly ADP-ribose polymerase; PCNA, proliferating cell nuclear antigen; P-gP, P-glycoprotein; PI3K, phosphoinositide 3-kinase; PL, phospholipid; p-Rb, phosphorylated retinoblastoma protein; PRDX, peroxiredoxin; ROS, reactive oxygen species; SOD, Superoxide Dismutase; STAT, signal transducer and activator of transcription; TG, triglyceride; TC, cholesterol total; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor n Correspondence to: Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai 200003, China. Tel.: þ 86 21 81885476; fax: þ 86 21 63520020. E-mail addresses: [email protected] (P.-K. Wei), [email protected] (X.-Q. Yue). http://dx.doi.org/10.1016/j.jep.2015.05.032 0378-8741/& 2015 Published by Elsevier Ireland Ltd.
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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4. Clinical trials of phlegm-eliminating herbs for the treatment of cancer. 5. Effects on inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Regulation of metabolic syndrome within the host. . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Cancer is considered to be the second leading cause of human death. It is unsatisfactory that in the past decades, the treatment for cancer has not progressed as fast as it was expected, as only 50% of newly diagnosed patients could be cured even today (Arends, 2010). Pathogenesis of cancer relates to proliferation, apoptosis, inflammation, internal environment, etc. (Wolchok and Chan, 2014). It is a complex process involving a multitude of factors including tumor cells themselves, the interactions between tumor cells and their microenvironments, as well as the interactions between tumor cells and the host's immunity. Focusing on any single goal may bring limited benefits such as targeted treatment drugs. The mechanisms of cancer should be further studied. Some studies have indicated that there are common molecular properties and biological programs among cancer, inflammation, and metabolic diseases, which may contribute to the epidemiological connections between cancer and other particular diseases (Hirsch et al., 2010). According to the theories on traditional Chinese medicine (TCM), phlegm refers not only to phlegm in the respiratory tract but also to the pathological metabolites in vivo. It plays an important role in the occurrence and development of cancer (Shi et al., 2012). TCM proposes that tumors result from the interactions among phlegm obstruction, qi stagnation, blood stasis and heat. Phlegm obstruction is believed to play a dominant role in tumor formation. TCM holds that phlegm, which results from the abnormal transformation of fluid-humor, is a pathologic metabolite that can be produced by diseases and other factors that are related to fluid-humor. For example, qi deficiency contributes to the accumulation of dampness into phlegm, and qi stagnation causes water retention, which in turn results in the production of phlegm. In addition, heat can boil fluid-humor, which condenses into phlegm. When phlegm is coagulated through the malfunctioning of fluid-humor, it further blocks meridians and collaterals, thus slowing down the circulation of qi, blood, and fluid-humor. Over time, the abnormal fluid-humor coagulates into a tumor. Studies have increasingly demonstrated the effectiveness of herbs in treating cancers (Kaefer and Milner, 2008). Conventionally, phlegmeliminating herbs, with the function of transforming phlegm, are commonly used to dissolve phlegm caused by common cold and internal diseases. They are also useful for epilepsy, wind stroke, and cancer. Recently, modern pharmacological studies have indicated that many of these herbs or bioactive spices are likely to contain anticancer active ingredients. In the current review, the potential anticancer mechanisms and clinical trials regarding the phlegm-eliminating herbs are summarized. Peer-reviewed articles were selected through the scientific databases MEDLINE, PubMed, and Google Scholar with the keywords including herb, cancer, phlegm, TCM, and phytochemical.
2. Anticancer activities of phlegm-eliminating herbs in vitro Pharmacological studies have revealed that some phlegmeliminating herbs contain active ingredients, the antitumor effects of which are reflected in many aspects such as induction of apoptosis,
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prevention of invasion and metastasis, and the reduction of resistance to chemotherapeutic drug (Table 1). 2.1. Apoptosis-inducing and anti-proliferative effects Disorder of apoptosis is one of the key characteristics of tumor cells. Caspase and cell cycle arrest are important in apoptosis. Induction of apoptosis in tumor cell is an important aspect of most antitumor studies (Debatin, 1999). With regard to induction, many ingredients of phlegm-eliminating herbs are likely to play a role. Citrus reticulata Blanco is one of the most important TCM herbs for eliminating phlegm. With the effect on circulating qi, drying dampness and transforming phlegm, it is used to treat cough and cancer in TCM practice. Current studies have indicated that the extracts or constituents of C. reticulata Blanco have anticancer effects on several tumor cell lines (Silalahi, 2002; Arias and Ramon-Laca, 2005), and its mechanism involving induction of apoptosis was demonstrated on human leukemic HL-60 (Hirano et al., 1995), gastric cancer (Kim et al., 2005; Lee et al., 2012b), colorectal cancer (Zheng et al., 2002), and lung cancer cells (Xiao et al., 2009). It is believed that the main active ingredients of C. reticulata Blanco are flavonoids, particularly polymethoxyflavones (PMFs), which are reported to have a role in inducing an increased level of intracellular Ca2 þ and thus activating Ca2 þ -dependent apoptotic proteases, and modulating key signaling proteins related to cell proliferation and apoptosis (Sergeev et al., 2007; Qiu et al., 2010). Similarly, Platycodon grandiflorus (Jacq.) A. DC., a common food and medicine in China, Korea and Japan, is another TCM herb for eliminating phlegm. As it is an expectorant and has antiinflammatory effects, it is used to treat cough with profuse sputum, pharyngitis, etc. As reported, the extract of P. grandiflorus (Jacq.) A. DC. can induce apoptosis in SKOV-3 human ovarian tumor cells (Hu et al., 2010), while platycodon D from the roots of P. grandiflorus (Jacq.) A. DC. has the similar effect on inducing apoptosis in MCF-7 human breast tumor cells (Yu and Kim, 2010) and U937 human leukemia cells (Shin et al., 2009). The possible mechanism is associated with the production of reactive oxygen species, activation of caspase-3, mitochondrial-dependent pathway, etc. Laminaria japonica Aresch is widely used to treat thyroid tumor, lymph node tuberculosis, etc. in China and Japan, due to its effects of softening hardness and dissipating bind. According to the previous studies, glycoprotein, a constituent of L. japonica Aresch could induce cell apoptosis via multiple pathways such as the Fas signaling pathway, the mitochondrial pathway, cell cycle arrest, downregulation of telomerase activity, prostaglandin E2 synthesis, etc. (Go et al., 2010; Han et al., 2011). Overall, these data suggest that many types of phlegmeliminating herbs or their ingredients can induce apoptosis of several tumor cells, while some other herbs and some spices can inhibit special tumor cells. Fritillaria ussuriensis Maxim., with heatclearing, phlegm-transforming effects, is usually used to treat cough in TCM practice. One study has indicated that verticinone from the bulbus of F. ussuriensis Maxim., has an effect on inducing apoptosis in malignant human oral keratinocytes through a caspase pathway mediated by mitochondrial damage and G0/G1 cell cycle arrest (Yun et al., 2008).
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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Table 1 Phlegm-eliminating herbs, phytochemicals with antitumor effects. Latin name
Family name
Pinyin
Compounds/extract
Anticancer mechanism
Citrus reticulata Blanco
Rutaceae
Chenpi
Extract
Mouse model of ↓ Tumor growth, Bcl2↑BAX, caspase-3 pathway FAP (in vivo) SNU668 (in vitro) (tumorigenesis, survival)
↓NO, iNOS
PMFs
↓ MMP-2, MMP-9, VEGF, cyclin D1, CDK-2, p-Rb, K-ras, tumor growth↑Apoptosis, intracellular Ca2 þ , P21, caspases-3, -8, cleaved PARP (tumorigenesis, survival, and migration) ↑apoptosis, G2, S/M ↓G1, PI3K/AKT (survival, multidrug resistance)
↓NOS, iNOS, COX-2, cyclooxygenase, NF-κB, STAT3 (in vivo)
Tangeretin
Cancer cell lines
Human prostate xenograft tumors, AOM-induced colonic tumorigenesis (in vivo) MCF-7, HCT-116, HT-29, H1299 (in vitro) HL-60, 2780/CP70, 2008/C13 (in vitro)
↓MMP1, MMP-2, MMP9, TIMP-1, replicating DNA synthesis, peritoneal dissemination (invasion and metastasis, survival)
↓ P-gP (multidrug resistance)
Human colon cell Caco2, CEM/ ADR5000 (in vitro)
Extract
↓ Bcl-2, the adhesion of tumor cells to the basement membrane ↑Bax, caspase-3,-8,-9, NK, survival time, mitochondrial cytochrome c to cytosol (survival, tumorigenesis, and metastasis) ↓number of surface lung tumors (tumorigenesis)
SKOV-3 (in vitro) B16-F10, Lung cancer (in vitro and vivo)
Saponins
Platycodin A, C, deapioplatycodin D Platycodin D
Laminaria japonica Aresch
Alariaceae
Kunbu
Hirano et al. (1995), Arafa et al. (2009) Manthey et al. (2008)
Rooprai et al. (2001), Sato et al. (2002), Lee et al. (2011a), Zheng et al. (2002) and Minagawa et al. (2001) Lee et al. (2011b)
↓ IL-1β, IL-6, TNFα↑CD4, CD8, albumin (in vivo)
Limonin
Lung tumorigenesis (in vivo)
U937, MCF-7 ↑ROS, caspase-3, -8, -9, PARP, BAX, ERK1/2, JNK1/2, (in vitro) P38, Egr-1↓Bcl-2 (survival)
Laminaria japonica
Anticoagulant (tumorigenesis)
Sarcoma M-1 (in vivo)
Glycoprotein
HT-29, AGS DNA fragmentation, sub(in vitro) G1 arrest↑caspase-3, -9, BAX, ROS, ERK1/2, JNK1/2, P38 ↓PARP, CDK2, cyclin E, cyclin D1, PCNA, E2F-1, p-Rb, Bcl-2, COX2, SP1, c-Myc, hTERT (survival)
References
Jung et al. (2007), Fan et al. (2007) and Kim et al. (2005) Lai et al. (2013, 2011), Sergeev et al. (2007), Qiu et al. (2010) and Xiao et al. (2009)
IPMA-E, IPSH-OA2, IPMC-A3, AMHFBGM, HT-1080, AGS, human colon cancer cells (in vitro) TMK-1 (in vivo)
Hesperidin
Campanulaceae Jiegeng Platycodon grandiflorus (Jacq.) A. DC.
Antiobesity
Rat carrageenan/ paw edema and mouse lipopolysaccharide challenge assay (in vivo)
3',4',3,5,6,7,8heptamethoxyflavone (HMF)
Nobiletin
Antiinflammation
↓Body weight, serum glucose, serum insulin ↑TGR5 (in vivo) ↑ AMPK/ ACC↓TC, TG, FABP mRNA, TC, leptin, resistin, MCP-1 (in vivo) ↓ PL, TG, ↑ p38/MAPK, Akt, TC, AMPK, CaMK II, NO, eNOS (in vitro) intestinal absorption (in vivo) ↓ PL (in vitro) ↓ PL ↓NF-κB, iNOS, COX2 (in vitro and (in vitro) vivo)
El-Readi et al. (2010) and Ono et al. (2011)
Hu et al. (2010), Lee et al. (2006a), Park et al. (2007), Lee et al. (2012a) and Kim et al (2000) Han et al (2000), Kim et al. (2010) and Lee et al. (2006b) Xu et al. (2005) Shin et al. (2009), Yu et al. (2010), Chung et al. (2008) and Xu et al. (2005) Starosel'skaia et al. (2008) Go et al. (2010) and Han et al. (2011)
Fucoidan
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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Table 1 (continued ) Latin name
Family name
Sargassum Sargassaceae pallidum (Turn.)C. Ag Pinellia ternate (Thunb.) Breit.
Liliaceae Fritillaria thunbergii Miq. Fritillaria Liliaceae ussuriensis Maxim.
Pinyin
Compounds/extract
Anticancer mechanism
Cancer cell lines
Antiinflammation
Antiobesity
References
↓TC, LDL-C ↑HDL-C (in vivo)
Huang et al. (2010)
Haizao
aqueous extract
Gastric cancer (in vivo)
↑IL-2, IL-4,IL-10 ↓IL-6, IL-1β,TNF-α
Zhang et al. (2012)
Banxia
Polysaccharide
Ehrlich ascites
↑serum SOD, MDA and GSH-Px (in vivo)
Li et al. (2013)
Zhebeimu
Trypsin inhibitor
↓ Proliferation
Alkaloid
↓ MDR1 mRNA, P-gP (survival and multidrug resistance) Mitochondrial damage G0/ Oral keratinocytes (in vitro) G1 cell cycle arrest (survival)
Pingbeimu Verticinone
BGC-823 (in vitro and vivo) A549/DDP (in vitro and vivo)
Zu et al. (2014) Li et al. (2013)
Yun et al. (2008)
Table 2 Phlegm-eliminating formulas with antitumor effects. Formula name
Anticancer mechanism
Cancer
References
Xiaotan Sanjie prescription Yiqichutan method Jinlongshe
↓VEGF-C, VEGFR-3, LVLD (tumor growth and metastasis) ↓PRDX-1, PRDX-6 (tumor growth and metastasis) ↑Survival time
Gastric cancer (in vivo) Lewis lung cancer (in vivo) Gastric cancer patients
Pang et al. (2011) Lin et al. (2011) Li and Wei (2001)
Besides apoptosis, infinite proliferation is another main characteristic of tumor cell, which results in its immortalization. One study has indicated that verticinone from F. ussuriensis Maxim. could inhibit the proliferation of the immortalized and malignant oral keratinocytes in a dose- and time-dependent manner (Yun et al., 2008). The trypsin inhibitor isolated from Pinellia ternate (Thunb.) Breit. was reported to have an inhibitory effect on proliferation of BGC-823 cells in vitro and tumor growth in mice (Zu et al., 2014). 2.2. Prevention of tumor invasion and metastasis Invasion and metastasis are important characteristics of tumor cells and may be the main causes of cancer death. The activation of matrix metalloproteinase (MMP) is mainly involved in the invasion and metastatic process because of the degradation of extracellular matrix. In the MMP family, MMP-1, MMP-2, and MMP-9 are the most important. Another core step in metastasis is the adhesion to endothelial cells (Kang et al., 2008; Hu et al., 2011). Some bioactive ingredients of phlegm-eliminating herbs have been proven to have a preventive effect on tumor invasion and metastasis. Nobiletin is one of the active components of C. reticulata Blanco and was proven to inhibit metastasis in vitro (Rooprai et al., 2001; Sato et al., 2002). Further studies have indicated that it can reduce invasion and migration of AGS cells, and inhibit the activation of focal adhesion kinase and phosphoinositide-3-kinase/Adams Kara Taylor (PI3K/Akt) involved in the downregulation of the enzyme, protein expression, messenger RNA levels of MMP-1, MMP-2 and MMP-9 (Lee et al., 2011a). After dissociation, tumor cells need to adhere to endothelial cells at once, and then these tumor cells escape into vessels. The aqueous extract of the P. grandiflorus (Jacq.) A. DC. can inhibit
tumor invasion and metastasis, possibly by inhibiting the adhesion of tumor cells to the basement membrane and activating natural killer cells (Lee et al., 2006a). 2.3. Synergies with chemotherapy and reduced resistance to chemotherapy Multidrug resistance (MDR) is one of the important causes of failure of chemotherapy against cancers. The main mechanism of MDR involves overproduction of P-glycoprotein (P-gp), a member of membrane-bound ATP-binding cassette (Jeong et al., 2011). It can transport intracellular drug outside the cell by active ATP pump, leading to weakened effect of drug resulting in MDR. This is considered as the most classic pathway of MDR. Interestingly, tangeretin, a constituent of C. reticulata Blanco, has effects not only on preventing cancer but also on enhancing the efficacy of chemotherapy. It can sensitize cisplatin-resistant human ovarian cancer cells by downregulating the PI3K/Akt signaling pathway (Arafa el et al., 2009). Limonin and other secondary metabolites from citrus species could be considered as good candidates for the development of novel P-gp reversal agents (El-Readi et al., 2010). Fritillaria thunbergii Miq., with heat-clearing, phlegm-transforming and bind-dissipating effects, is used to treat thyroid tumor, lymphadenectasis, etc. Similar to liminon, the total alkaloid from F. thunbergii Miq. enhances the accumulation and efficacy of chemotherapeutic agents by decreasing the expression of MDR1 mRNA and P-gp (Li et al., 2013). 3. Antitumor activities of phlegm-eliminating herbs in vivo Animal models of chemical carcinogenesis and tumor-bearing mice models are usually used in vivo antitumor study. Some
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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studies have shown that phlegm-eliminating herbs have antitumorigenic properties or antitumor effects. C. reticulata Blanco has shown inhibiting effects on tumorigenesis, growth, and dissemination. A study has shown its role in a mouse model of human familial adenomatous polyposis, and increased apoptosis may have contributed to this effect (Fan et al., 2007). Flavonoid nobiletin, the main component of C. reticulata Blanco, inhibited peritoneal dissemination of human gastric carcinoma in severe combined immunodeficiency mice (Minagawa et al., 2001). Furthermore, Gold Lotion, an extract from multiple varieties of C. reticulata Blanco containing abundant flavonoids including a large percentage of PMFs, was proven to not only suppress azoxymethaneinduced colonic tumorigenesis effectively (Lai et al., 2011), but also reduce both the weights (57–100% inhibition) and volumes (78–94% inhibition) of the tumors in a human prostate tumor xenograft mouse model without any observed toxicity by both intraperitoneal injection and oral administration. These inhibitory effects were accompanied by mechanistic downregulation of the protein levels of inflammatory enzymes [inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)], metastasis (MMP-1, MMP-2, and MMP9), angiogenesis [vascular endothelial growth factor (VEGF)], and proliferative molecules, as well as by the induction of apoptosis in prostate tumors (Lai et al., 2013). Saponins derived from the roots of P. grandiflorus (Jacq.) A. DC. has chemopreventive effect on 4-(methylnitrosamino)-1-(3-pyrigy1)butanone-induced lung tumorigenesis in A/J mice (Lee et al., 2006b). P. ternate (Thunb.) Breit., which is a type of herb that warms and transforms cold phlegm, is used to treat cancer or expectoration usually. The polysaccharide derived from the herb showed an inhibitory effect on Ehrlich ascites (Li et al., 2013). Fucans, a constituent of L. japonica Aresch, was shown to exert anticoagulant action to inhibit carcinogenesis (Starosel'skaia et al., 2008). The phlegm-eliminating formulas are more frequently used to treat cancer in TCM practice. Cancer often involves a mixture of deficiency and repletion, and TCM theory attributes the formation of phlegm partly to deficiency of spleen qi (Shi et al., 2012). The phlegm-eliminating formulas contain not only phlegmeliminating herbs, but also the herbs from other categories to address the root cause of phlegm production such as spleen deficiency, or other complicating clinical factors such as blood stasis and qi stagnation. Hence some spleen strengthening herbs such as Poria cocos (Schw.) Wolfe are widely used in phlegmeliminating formulas, even though they do not belong to the category of phlegm-eliminating herbs. Some studies have shown the potent anticancer effects of phlegm-eliminating formulas in vivo (Table 2). A study indicated that Xiaotan Sanjie prescription, a phlegm-eliminating formula, can decrease the mRNA and protein expressions of vascular endothelial growth factor (VEGF)-C and vascular endothelial growth factor receptor (VEGFR)-3 as well as lymphatic micro-vessel density level in MKN-45 human gastric cancer xenograft models (Pang et al., 2011). Another example comes from the high-dose Yiqi Chutan prescription, a phlegm-eliminating formula, that can remarkably inhibit the growth and metastasis of Lewis lung carcinoma in mice with spleen deficiency syndrome, prolonging their survival period, and its mechanism is possibly related to the reduction of overexpressed peroxiredoxin-1 (PRDX-1) and PRDX-6 (Lin et al., 2011).
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In a clinical trial involving 104 patients with advanced gastric cancer, the median survival time of the patients in the TCM group who received Jinlongshe was 12.4 months, while that of patients in the chemotherapy group who received ELF (Vp16 þCF þ5-FU) was 6.71 months (Li and Wei, 2001). In another prospective, multicenter, randomized, controlled clinical trial involving 202 patients with non-small cell lung cancer (NSCLC) patients at stage III or IV, the median survival time of NSCLC patients who were treated with the TCM method of invigorating qi and removing the phlegm was 9 months, and that of the NSCLC patients who were treated with TCM method of invigorating qi and removing the phlegm combined with chemotherapy (NP/VP, three period of treatment) can reach up to 12 months (Zhou et al., 2005).
5. Effects on inflammation Inflammation plays an important role in the development and progression of cancers. It can not only activate oncogenes and inhibit tumor suppressor genes, but also regulate transcription factors, causing the cells to proliferate indefinitely and also angiogenesis, resulting in premalignant cells (Mantovani et al., 2008; Grivennikov et al., 2010). These inflammatory factors can further act as inducers, promoting the recurrence of tumor and metastasis of cancer cell invasion (Zhou et al., 2010). Nuclear factor-kappaB (NF-κB) is usually viewed as a “critical component to bridge inflammation and cancer” because it can induce more than 200 genes related to inflammation and cancer (Yoon and Baek, 2005). Besides NF-κB, COX-2 and iNOS also have important roles in inflammation and cancer process. These are often activated by several signaling pathways such as PI3K/Akt, p38/mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), etc. Many studies have revealed anti-inflammatory effect of a variety of phlegm-eliminating herbs and spices, which may be the mechanism of their anticancer effects. Sargassum pallidum (Turn.)C. Ag has the effects on softening hardness and dissipating bind in TCM. It also shows antioxidant and anti-inflammatory effects in gastric cancer rats (Zhang et al., 2012). Extracts of C. reticulata Blanco and its chemical species have been shown to exhibit anti-inflammatory activity in Raw 264.7 macrophage cells (Jung et al., 2007) and the rat carrageenan/paw edema and mouse lipopolysaccharide challenge assays (Manthey and Bendele, 2008). Moreover, hesperidin, which is also derived from C. reticulata Blanco, can reduce the concentration of serum cytokines [interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNFα)], enhance immunocompetence, produce beneficial effects on their nutritional status, and decrease the irradiation-induced inflammation in the radiation mouse group (Lee et al., 2011b). It exhibits anti-inflammatory activity by inhibiting the expression of hypoxia-inducible factor-1α, producing inflammatory cytokine from mast cells (Choi et al., 2007). Another example is that saponins from P. grandiflorus (Jacq.) A. DC could inhibit TNF-α-induced expression of adhesion molecules in human endothelial cells; stimulate the phosphorylation of endothelial nitric oxide synthase, and production of NO via the activation of PI3K/Akt, MAPK, AMPK, and Ca2 þ /calmodulin-dependent protein kinase II (Kim et al., 2010). Platycodin D, isolated from P. grandiflorus (Jacq.) A. DC, exerts a suppressive effect on the activation of NF-κB at the transcriptional level (Chung et al., 2008).
4. Clinical trials of phlegm-eliminating herbs for the treatment of cancer
6. Regulation of metabolic syndrome within the host
An increasing number of clinical studies have indicated that TCM could improve quality of life, prolong the survival time, reduce recurrence, metastasis, etc. in patients with cancer (Molassiotis et al., 2009).
The host's internal environment, as has been proven in some studies, also plays an important role in the occurrence of tumor and metastasis. The abnormal host environment, typified by metabolic syndrome (MS), has become the new focus in tumor
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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biology in recent years. For example, studies suggest that MS, which includes symptoms such as obesity, hyperlipidemia, hyperglycemia, atherosclerosis, etc., is considered as a contributing factor to cancer as well as cardiovascular diseases (Halmos and Suba, 2008). In fact, it can be regarded as a high-risk state for particular tumors (Cowey and Hardy, 2006), raising the risk of cancer and thereafter affecting the relevant prognosis (Hursting and Berger, 2010; Legakis and Syrigos, 2010). On the other hand, the drugs designed to combat metabolic diseases such as metformin and simvastin can inhibit the tumor growth in xenografts which were injected with transformed non-cancerous immortalized breast cells (MCF-10A ER-Src cells) (Hirsch et al., 2010). Thus, MS is closely related to the occurrence, progression, and prognosis of cancer, although the specific mechanism remains unclear. Studies have suggested that the extracts or constituents of P. grandiflorus (Jacq.) A. DC (Park et al., 2007) and L. japonica Aresch (Huang et al., 2010) can reduce the plasma levels of triglyceride, total cholesterol, and low-density lipoprotein–cholesterol, and increase the plasma level of high-density lipoprotein–cholesterol in hyperlipidemic rats. Moreover, citrus limonoid from C. reticulata Blanco has been reported to have antiobesity and antihyperglycemic effects on mice fed on a high-fat diet (Ono et al., 2011). The powder of P. grandiflorus (Jacq.) A. DC can ameliorate obesity and insulin resistance, regulate lipid metabolism in obese mice via the activation of AMPK/ACC pathways and reduction of pancreatic lipase in vivo (Kim et al., 2000; Lee et al., 2012a). The antiobesity effects of saponins, the aqueous extract of P. grandiflorus (Jacq.) A. DC, may be due, in part, to the inhibition of intestinal absorption (Han et al., 2000). Further purification of active components yielded such triterpenoidal saponins as platycodin A, C, D, and deapioplatycodin D, which exhibited significant inhibitory effects on phospholipid in vitro (Xu et al., 2005).
7. Conclusion The relationships between cancer and other diseases such as inflammation and metabolic disease show the necessity for comprehensive treatment of cancer. The above-mentioned studies suggest that traditional Chinese phlegm-eliminating herbs and their active ingredients are effective in treating cancer by inducing apoptosis, anti-proliferation, preventing tumor invasion and metastasis, and reducing resistance to chemotherapy. In addition, phlegm-eliminating herbs and their active ingredients have antiinflammatory and anti-metabolic syndrome effects. Despite the fact that the phlegm-eliminating herbs and formulas are widely used to treat cancer patients in China, more controlled clinical research about them has yet to be conducted. We suggest that the phlegm-eliminating herbs and ingredients are potential candidates for anticancer treatment and cancer prevention by playing a comprehensive role.
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Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview Li-Juan Xiu, Da-Zhi Sun, Jian-Peng Jiao, Bing Yan, Zhi-Feng Qin, Xuan Liu, Pin-Kang Wei n, Xiao-Qiang Yue n Department of Traditional Chinese Medicine, Shanghai Changzheng Hospital, Shanghai 200003, China
art ic l e i nf o
a b s t r a c t
Article history: Received 12 December 2014 Received in revised form 10 May 2015 Accepted 10 May 2015
Ethonopharmacological relevance: Cancer is considered to be the second leading cause of human death. It is unsatisfactory that in the past decades, the treatment for cancer has not progressed as fast as it was expected, as only 50% of newly diagnosed patients could be cured even today. The development of cancer is a multifactorial process, involving tumor cells themselves, the interactions between tumor cells and their microenvironments, as well as the interactions between tumor cells and the host's immunity. Focusing on any single goal may bring limited benefits. Aim and methods of the study: Phlegm-eliminating herbs, which can reduce phlegm and eliminate pathological metabolites, are commonly used to treat cancer in China. However, the underlying molecular targets and efficacy of herbal medicines in cancer treatment still remain unclear. In this study, we reviewed the potential anticancer mechanisms of some phlegm-eliminating herbs and their active ingredients from the articles through such scientific databases as MEDLINE, PubMed, and Google Scholar. Results: We found that the anticancer mechanisms of phlegm-eliminating herbs and ingredients include inducing apoptosis, anti-proliferation, preventing tumor invasion and metastasis, and reducing resistance to chemotherapy. In addition, some phlegm-eliminating herbs and their ingredients have antiinflammatory and anti-metabolic syndrome effects. Conclusions: We suggest that the phlegm-eliminating herbs and ingredients are potential candidates for anticancer treatment and cancer prevention by playing a comprehensive role. & 2015 Published by Elsevier Ireland Ltd.
Chemical compounds studied in this article: 3',4',3,5,6,7,8-heptamethoxyflavone (PubChem CID: 150893) deapioplatycodin D (PubChem CID: 86578026) glycoprotein (PubChem CID: 439212) hesperidin (PubChem CID: 10621) limonin (PubChem CID: 179651) nobiletin (PubChem CID: 72344) platycodin D (PubChem CID: 162859) tangeretin (PubChem CID: 68077) verticinone (PubChem CID: 167691) Keywords: Cancer Phlegm Traditional Chinese medicine Herb
Contents 1. 2.
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anticancer activities of phlegm-eliminating herbs in vitro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Apoptosis-inducing and anti-proliferative effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Prevention of tumor invasion and metastasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Synergies with chemotherapy and reduced resistance to chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Antitumor activities of phlegm-eliminating herbs in vivo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: AMPK, AMP-activated protein kinase; ACC, acetyl-CoAcarboxylase; COX, cyclooxygenase; CDK, cyclin-dependent kinase; CaMK, Ca2 þ /calmodulindependent protein kinase; CPT, Cholinephosphotransferase; Egr, early growth response gene; ERK, extracellular signal-related kinase; GSH-Px, Glutathione peroxidase; HDL-C, High Density Lipoprotein Cholesterol; hTERT, human telomerase reverse transcriptase; HPV, human papillomavirus; iNOS, inducible nitric oxide synthase; IL, interleukin; JNK, c-Jun N-terminal kinase; K-ras, Kirsten RAS; LDL-C, low density lipoprotein-cholesterol; MAPK, mitogen-activated protein kinases; MCP, Membrane cofactor protein; MDA, malondialdehyde, multidrug resistance; MMP, matrix metalloproteinase; NO, nitrie oxide; NF-κB, nuclear factor-kappaB; NK, nature killer cell; PARP, poly ADP-ribose polymerase; PCNA, proliferating cell nuclear antigen; P-gP, P-glycoprotein; PI3K, phosphoinositide 3-kinase; PL, phospholipid; p-Rb, phosphorylated retinoblastoma protein; PRDX, peroxiredoxin; ROS, reactive oxygen species; SOD, Superoxide Dismutase; STAT, signal transducer and activator of transcription; TG, triglyceride; TC, cholesterol total; TIMP, tissue inhibitor of metalloproteinase; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor n Correspondence to: Changzheng Hospital, Second Military Medical University, No. 415 Fengyang Road, Shanghai 200003, China. Tel.: þ 86 21 81885476; fax: þ 86 21 63520020. E-mail addresses: [email protected] (P.-K. Wei), [email protected] (X.-Q. Yue). http://dx.doi.org/10.1016/j.jep.2015.05.032 0378-8741/& 2015 Published by Elsevier Ireland Ltd.
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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4. Clinical trials of phlegm-eliminating herbs for the treatment of cancer. 5. Effects on inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Regulation of metabolic syndrome within the host. . . . . . . . . . . . . . . . . 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Cancer is considered to be the second leading cause of human death. It is unsatisfactory that in the past decades, the treatment for cancer has not progressed as fast as it was expected, as only 50% of newly diagnosed patients could be cured even today (Arends, 2010). Pathogenesis of cancer relates to proliferation, apoptosis, inflammation, internal environment, etc. (Wolchok and Chan, 2014). It is a complex process involving a multitude of factors including tumor cells themselves, the interactions between tumor cells and their microenvironments, as well as the interactions between tumor cells and the host's immunity. Focusing on any single goal may bring limited benefits such as targeted treatment drugs. The mechanisms of cancer should be further studied. Some studies have indicated that there are common molecular properties and biological programs among cancer, inflammation, and metabolic diseases, which may contribute to the epidemiological connections between cancer and other particular diseases (Hirsch et al., 2010). According to the theories on traditional Chinese medicine (TCM), phlegm refers not only to phlegm in the respiratory tract but also to the pathological metabolites in vivo. It plays an important role in the occurrence and development of cancer (Shi et al., 2012). TCM proposes that tumors result from the interactions among phlegm obstruction, qi stagnation, blood stasis and heat. Phlegm obstruction is believed to play a dominant role in tumor formation. TCM holds that phlegm, which results from the abnormal transformation of fluid-humor, is a pathologic metabolite that can be produced by diseases and other factors that are related to fluid-humor. For example, qi deficiency contributes to the accumulation of dampness into phlegm, and qi stagnation causes water retention, which in turn results in the production of phlegm. In addition, heat can boil fluid-humor, which condenses into phlegm. When phlegm is coagulated through the malfunctioning of fluid-humor, it further blocks meridians and collaterals, thus slowing down the circulation of qi, blood, and fluid-humor. Over time, the abnormal fluid-humor coagulates into a tumor. Studies have increasingly demonstrated the effectiveness of herbs in treating cancers (Kaefer and Milner, 2008). Conventionally, phlegmeliminating herbs, with the function of transforming phlegm, are commonly used to dissolve phlegm caused by common cold and internal diseases. They are also useful for epilepsy, wind stroke, and cancer. Recently, modern pharmacological studies have indicated that many of these herbs or bioactive spices are likely to contain anticancer active ingredients. In the current review, the potential anticancer mechanisms and clinical trials regarding the phlegm-eliminating herbs are summarized. Peer-reviewed articles were selected through the scientific databases MEDLINE, PubMed, and Google Scholar with the keywords including herb, cancer, phlegm, TCM, and phytochemical.
2. Anticancer activities of phlegm-eliminating herbs in vitro Pharmacological studies have revealed that some phlegmeliminating herbs contain active ingredients, the antitumor effects of which are reflected in many aspects such as induction of apoptosis,
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prevention of invasion and metastasis, and the reduction of resistance to chemotherapeutic drug (Table 1). 2.1. Apoptosis-inducing and anti-proliferative effects Disorder of apoptosis is one of the key characteristics of tumor cells. Caspase and cell cycle arrest are important in apoptosis. Induction of apoptosis in tumor cell is an important aspect of most antitumor studies (Debatin, 1999). With regard to induction, many ingredients of phlegm-eliminating herbs are likely to play a role. Citrus reticulata Blanco is one of the most important TCM herbs for eliminating phlegm. With the effect on circulating qi, drying dampness and transforming phlegm, it is used to treat cough and cancer in TCM practice. Current studies have indicated that the extracts or constituents of C. reticulata Blanco have anticancer effects on several tumor cell lines (Silalahi, 2002; Arias and Ramon-Laca, 2005), and its mechanism involving induction of apoptosis was demonstrated on human leukemic HL-60 (Hirano et al., 1995), gastric cancer (Kim et al., 2005; Lee et al., 2012b), colorectal cancer (Zheng et al., 2002), and lung cancer cells (Xiao et al., 2009). It is believed that the main active ingredients of C. reticulata Blanco are flavonoids, particularly polymethoxyflavones (PMFs), which are reported to have a role in inducing an increased level of intracellular Ca2 þ and thus activating Ca2 þ -dependent apoptotic proteases, and modulating key signaling proteins related to cell proliferation and apoptosis (Sergeev et al., 2007; Qiu et al., 2010). Similarly, Platycodon grandiflorus (Jacq.) A. DC., a common food and medicine in China, Korea and Japan, is another TCM herb for eliminating phlegm. As it is an expectorant and has antiinflammatory effects, it is used to treat cough with profuse sputum, pharyngitis, etc. As reported, the extract of P. grandiflorus (Jacq.) A. DC. can induce apoptosis in SKOV-3 human ovarian tumor cells (Hu et al., 2010), while platycodon D from the roots of P. grandiflorus (Jacq.) A. DC. has the similar effect on inducing apoptosis in MCF-7 human breast tumor cells (Yu and Kim, 2010) and U937 human leukemia cells (Shin et al., 2009). The possible mechanism is associated with the production of reactive oxygen species, activation of caspase-3, mitochondrial-dependent pathway, etc. Laminaria japonica Aresch is widely used to treat thyroid tumor, lymph node tuberculosis, etc. in China and Japan, due to its effects of softening hardness and dissipating bind. According to the previous studies, glycoprotein, a constituent of L. japonica Aresch could induce cell apoptosis via multiple pathways such as the Fas signaling pathway, the mitochondrial pathway, cell cycle arrest, downregulation of telomerase activity, prostaglandin E2 synthesis, etc. (Go et al., 2010; Han et al., 2011). Overall, these data suggest that many types of phlegmeliminating herbs or their ingredients can induce apoptosis of several tumor cells, while some other herbs and some spices can inhibit special tumor cells. Fritillaria ussuriensis Maxim., with heatclearing, phlegm-transforming effects, is usually used to treat cough in TCM practice. One study has indicated that verticinone from the bulbus of F. ussuriensis Maxim., has an effect on inducing apoptosis in malignant human oral keratinocytes through a caspase pathway mediated by mitochondrial damage and G0/G1 cell cycle arrest (Yun et al., 2008).
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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Table 1 Phlegm-eliminating herbs, phytochemicals with antitumor effects. Latin name
Family name
Pinyin
Compounds/extract
Anticancer mechanism
Citrus reticulata Blanco
Rutaceae
Chenpi
Extract
Mouse model of ↓ Tumor growth, Bcl2↑BAX, caspase-3 pathway FAP (in vivo) SNU668 (in vitro) (tumorigenesis, survival)
↓NO, iNOS
PMFs
↓ MMP-2, MMP-9, VEGF, cyclin D1, CDK-2, p-Rb, K-ras, tumor growth↑Apoptosis, intracellular Ca2 þ , P21, caspases-3, -8, cleaved PARP (tumorigenesis, survival, and migration) ↑apoptosis, G2, S/M ↓G1, PI3K/AKT (survival, multidrug resistance)
↓NOS, iNOS, COX-2, cyclooxygenase, NF-κB, STAT3 (in vivo)
Tangeretin
Cancer cell lines
Human prostate xenograft tumors, AOM-induced colonic tumorigenesis (in vivo) MCF-7, HCT-116, HT-29, H1299 (in vitro) HL-60, 2780/CP70, 2008/C13 (in vitro)
↓MMP1, MMP-2, MMP9, TIMP-1, replicating DNA synthesis, peritoneal dissemination (invasion and metastasis, survival)
↓ P-gP (multidrug resistance)
Human colon cell Caco2, CEM/ ADR5000 (in vitro)
Extract
↓ Bcl-2, the adhesion of tumor cells to the basement membrane ↑Bax, caspase-3,-8,-9, NK, survival time, mitochondrial cytochrome c to cytosol (survival, tumorigenesis, and metastasis) ↓number of surface lung tumors (tumorigenesis)
SKOV-3 (in vitro) B16-F10, Lung cancer (in vitro and vivo)
Saponins
Platycodin A, C, deapioplatycodin D Platycodin D
Laminaria japonica Aresch
Alariaceae
Kunbu
Hirano et al. (1995), Arafa et al. (2009) Manthey et al. (2008)
Rooprai et al. (2001), Sato et al. (2002), Lee et al. (2011a), Zheng et al. (2002) and Minagawa et al. (2001) Lee et al. (2011b)
↓ IL-1β, IL-6, TNFα↑CD4, CD8, albumin (in vivo)
Limonin
Lung tumorigenesis (in vivo)
U937, MCF-7 ↑ROS, caspase-3, -8, -9, PARP, BAX, ERK1/2, JNK1/2, (in vitro) P38, Egr-1↓Bcl-2 (survival)
Laminaria japonica
Anticoagulant (tumorigenesis)
Sarcoma M-1 (in vivo)
Glycoprotein
HT-29, AGS DNA fragmentation, sub(in vitro) G1 arrest↑caspase-3, -9, BAX, ROS, ERK1/2, JNK1/2, P38 ↓PARP, CDK2, cyclin E, cyclin D1, PCNA, E2F-1, p-Rb, Bcl-2, COX2, SP1, c-Myc, hTERT (survival)
References
Jung et al. (2007), Fan et al. (2007) and Kim et al. (2005) Lai et al. (2013, 2011), Sergeev et al. (2007), Qiu et al. (2010) and Xiao et al. (2009)
IPMA-E, IPSH-OA2, IPMC-A3, AMHFBGM, HT-1080, AGS, human colon cancer cells (in vitro) TMK-1 (in vivo)
Hesperidin
Campanulaceae Jiegeng Platycodon grandiflorus (Jacq.) A. DC.
Antiobesity
Rat carrageenan/ paw edema and mouse lipopolysaccharide challenge assay (in vivo)
3',4',3,5,6,7,8heptamethoxyflavone (HMF)
Nobiletin
Antiinflammation
↓Body weight, serum glucose, serum insulin ↑TGR5 (in vivo) ↑ AMPK/ ACC↓TC, TG, FABP mRNA, TC, leptin, resistin, MCP-1 (in vivo) ↓ PL, TG, ↑ p38/MAPK, Akt, TC, AMPK, CaMK II, NO, eNOS (in vitro) intestinal absorption (in vivo) ↓ PL (in vitro) ↓ PL ↓NF-κB, iNOS, COX2 (in vitro and (in vitro) vivo)
El-Readi et al. (2010) and Ono et al. (2011)
Hu et al. (2010), Lee et al. (2006a), Park et al. (2007), Lee et al. (2012a) and Kim et al (2000) Han et al (2000), Kim et al. (2010) and Lee et al. (2006b) Xu et al. (2005) Shin et al. (2009), Yu et al. (2010), Chung et al. (2008) and Xu et al. (2005) Starosel'skaia et al. (2008) Go et al. (2010) and Han et al. (2011)
Fucoidan
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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Table 1 (continued ) Latin name
Family name
Sargassum Sargassaceae pallidum (Turn.)C. Ag Pinellia ternate (Thunb.) Breit.
Liliaceae Fritillaria thunbergii Miq. Fritillaria Liliaceae ussuriensis Maxim.
Pinyin
Compounds/extract
Anticancer mechanism
Cancer cell lines
Antiinflammation
Antiobesity
References
↓TC, LDL-C ↑HDL-C (in vivo)
Huang et al. (2010)
Haizao
aqueous extract
Gastric cancer (in vivo)
↑IL-2, IL-4,IL-10 ↓IL-6, IL-1β,TNF-α
Zhang et al. (2012)
Banxia
Polysaccharide
Ehrlich ascites
↑serum SOD, MDA and GSH-Px (in vivo)
Li et al. (2013)
Zhebeimu
Trypsin inhibitor
↓ Proliferation
Alkaloid
↓ MDR1 mRNA, P-gP (survival and multidrug resistance) Mitochondrial damage G0/ Oral keratinocytes (in vitro) G1 cell cycle arrest (survival)
Pingbeimu Verticinone
BGC-823 (in vitro and vivo) A549/DDP (in vitro and vivo)
Zu et al. (2014) Li et al. (2013)
Yun et al. (2008)
Table 2 Phlegm-eliminating formulas with antitumor effects. Formula name
Anticancer mechanism
Cancer
References
Xiaotan Sanjie prescription Yiqichutan method Jinlongshe
↓VEGF-C, VEGFR-3, LVLD (tumor growth and metastasis) ↓PRDX-1, PRDX-6 (tumor growth and metastasis) ↑Survival time
Gastric cancer (in vivo) Lewis lung cancer (in vivo) Gastric cancer patients
Pang et al. (2011) Lin et al. (2011) Li and Wei (2001)
Besides apoptosis, infinite proliferation is another main characteristic of tumor cell, which results in its immortalization. One study has indicated that verticinone from F. ussuriensis Maxim. could inhibit the proliferation of the immortalized and malignant oral keratinocytes in a dose- and time-dependent manner (Yun et al., 2008). The trypsin inhibitor isolated from Pinellia ternate (Thunb.) Breit. was reported to have an inhibitory effect on proliferation of BGC-823 cells in vitro and tumor growth in mice (Zu et al., 2014). 2.2. Prevention of tumor invasion and metastasis Invasion and metastasis are important characteristics of tumor cells and may be the main causes of cancer death. The activation of matrix metalloproteinase (MMP) is mainly involved in the invasion and metastatic process because of the degradation of extracellular matrix. In the MMP family, MMP-1, MMP-2, and MMP-9 are the most important. Another core step in metastasis is the adhesion to endothelial cells (Kang et al., 2008; Hu et al., 2011). Some bioactive ingredients of phlegm-eliminating herbs have been proven to have a preventive effect on tumor invasion and metastasis. Nobiletin is one of the active components of C. reticulata Blanco and was proven to inhibit metastasis in vitro (Rooprai et al., 2001; Sato et al., 2002). Further studies have indicated that it can reduce invasion and migration of AGS cells, and inhibit the activation of focal adhesion kinase and phosphoinositide-3-kinase/Adams Kara Taylor (PI3K/Akt) involved in the downregulation of the enzyme, protein expression, messenger RNA levels of MMP-1, MMP-2 and MMP-9 (Lee et al., 2011a). After dissociation, tumor cells need to adhere to endothelial cells at once, and then these tumor cells escape into vessels. The aqueous extract of the P. grandiflorus (Jacq.) A. DC. can inhibit
tumor invasion and metastasis, possibly by inhibiting the adhesion of tumor cells to the basement membrane and activating natural killer cells (Lee et al., 2006a). 2.3. Synergies with chemotherapy and reduced resistance to chemotherapy Multidrug resistance (MDR) is one of the important causes of failure of chemotherapy against cancers. The main mechanism of MDR involves overproduction of P-glycoprotein (P-gp), a member of membrane-bound ATP-binding cassette (Jeong et al., 2011). It can transport intracellular drug outside the cell by active ATP pump, leading to weakened effect of drug resulting in MDR. This is considered as the most classic pathway of MDR. Interestingly, tangeretin, a constituent of C. reticulata Blanco, has effects not only on preventing cancer but also on enhancing the efficacy of chemotherapy. It can sensitize cisplatin-resistant human ovarian cancer cells by downregulating the PI3K/Akt signaling pathway (Arafa el et al., 2009). Limonin and other secondary metabolites from citrus species could be considered as good candidates for the development of novel P-gp reversal agents (El-Readi et al., 2010). Fritillaria thunbergii Miq., with heat-clearing, phlegm-transforming and bind-dissipating effects, is used to treat thyroid tumor, lymphadenectasis, etc. Similar to liminon, the total alkaloid from F. thunbergii Miq. enhances the accumulation and efficacy of chemotherapeutic agents by decreasing the expression of MDR1 mRNA and P-gp (Li et al., 2013). 3. Antitumor activities of phlegm-eliminating herbs in vivo Animal models of chemical carcinogenesis and tumor-bearing mice models are usually used in vivo antitumor study. Some
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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studies have shown that phlegm-eliminating herbs have antitumorigenic properties or antitumor effects. C. reticulata Blanco has shown inhibiting effects on tumorigenesis, growth, and dissemination. A study has shown its role in a mouse model of human familial adenomatous polyposis, and increased apoptosis may have contributed to this effect (Fan et al., 2007). Flavonoid nobiletin, the main component of C. reticulata Blanco, inhibited peritoneal dissemination of human gastric carcinoma in severe combined immunodeficiency mice (Minagawa et al., 2001). Furthermore, Gold Lotion, an extract from multiple varieties of C. reticulata Blanco containing abundant flavonoids including a large percentage of PMFs, was proven to not only suppress azoxymethaneinduced colonic tumorigenesis effectively (Lai et al., 2011), but also reduce both the weights (57–100% inhibition) and volumes (78–94% inhibition) of the tumors in a human prostate tumor xenograft mouse model without any observed toxicity by both intraperitoneal injection and oral administration. These inhibitory effects were accompanied by mechanistic downregulation of the protein levels of inflammatory enzymes [inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)], metastasis (MMP-1, MMP-2, and MMP9), angiogenesis [vascular endothelial growth factor (VEGF)], and proliferative molecules, as well as by the induction of apoptosis in prostate tumors (Lai et al., 2013). Saponins derived from the roots of P. grandiflorus (Jacq.) A. DC. has chemopreventive effect on 4-(methylnitrosamino)-1-(3-pyrigy1)butanone-induced lung tumorigenesis in A/J mice (Lee et al., 2006b). P. ternate (Thunb.) Breit., which is a type of herb that warms and transforms cold phlegm, is used to treat cancer or expectoration usually. The polysaccharide derived from the herb showed an inhibitory effect on Ehrlich ascites (Li et al., 2013). Fucans, a constituent of L. japonica Aresch, was shown to exert anticoagulant action to inhibit carcinogenesis (Starosel'skaia et al., 2008). The phlegm-eliminating formulas are more frequently used to treat cancer in TCM practice. Cancer often involves a mixture of deficiency and repletion, and TCM theory attributes the formation of phlegm partly to deficiency of spleen qi (Shi et al., 2012). The phlegm-eliminating formulas contain not only phlegmeliminating herbs, but also the herbs from other categories to address the root cause of phlegm production such as spleen deficiency, or other complicating clinical factors such as blood stasis and qi stagnation. Hence some spleen strengthening herbs such as Poria cocos (Schw.) Wolfe are widely used in phlegmeliminating formulas, even though they do not belong to the category of phlegm-eliminating herbs. Some studies have shown the potent anticancer effects of phlegm-eliminating formulas in vivo (Table 2). A study indicated that Xiaotan Sanjie prescription, a phlegm-eliminating formula, can decrease the mRNA and protein expressions of vascular endothelial growth factor (VEGF)-C and vascular endothelial growth factor receptor (VEGFR)-3 as well as lymphatic micro-vessel density level in MKN-45 human gastric cancer xenograft models (Pang et al., 2011). Another example comes from the high-dose Yiqi Chutan prescription, a phlegm-eliminating formula, that can remarkably inhibit the growth and metastasis of Lewis lung carcinoma in mice with spleen deficiency syndrome, prolonging their survival period, and its mechanism is possibly related to the reduction of overexpressed peroxiredoxin-1 (PRDX-1) and PRDX-6 (Lin et al., 2011).
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In a clinical trial involving 104 patients with advanced gastric cancer, the median survival time of the patients in the TCM group who received Jinlongshe was 12.4 months, while that of patients in the chemotherapy group who received ELF (Vp16 þCF þ5-FU) was 6.71 months (Li and Wei, 2001). In another prospective, multicenter, randomized, controlled clinical trial involving 202 patients with non-small cell lung cancer (NSCLC) patients at stage III or IV, the median survival time of NSCLC patients who were treated with the TCM method of invigorating qi and removing the phlegm was 9 months, and that of the NSCLC patients who were treated with TCM method of invigorating qi and removing the phlegm combined with chemotherapy (NP/VP, three period of treatment) can reach up to 12 months (Zhou et al., 2005).
5. Effects on inflammation Inflammation plays an important role in the development and progression of cancers. It can not only activate oncogenes and inhibit tumor suppressor genes, but also regulate transcription factors, causing the cells to proliferate indefinitely and also angiogenesis, resulting in premalignant cells (Mantovani et al., 2008; Grivennikov et al., 2010). These inflammatory factors can further act as inducers, promoting the recurrence of tumor and metastasis of cancer cell invasion (Zhou et al., 2010). Nuclear factor-kappaB (NF-κB) is usually viewed as a “critical component to bridge inflammation and cancer” because it can induce more than 200 genes related to inflammation and cancer (Yoon and Baek, 2005). Besides NF-κB, COX-2 and iNOS also have important roles in inflammation and cancer process. These are often activated by several signaling pathways such as PI3K/Akt, p38/mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), etc. Many studies have revealed anti-inflammatory effect of a variety of phlegm-eliminating herbs and spices, which may be the mechanism of their anticancer effects. Sargassum pallidum (Turn.)C. Ag has the effects on softening hardness and dissipating bind in TCM. It also shows antioxidant and anti-inflammatory effects in gastric cancer rats (Zhang et al., 2012). Extracts of C. reticulata Blanco and its chemical species have been shown to exhibit anti-inflammatory activity in Raw 264.7 macrophage cells (Jung et al., 2007) and the rat carrageenan/paw edema and mouse lipopolysaccharide challenge assays (Manthey and Bendele, 2008). Moreover, hesperidin, which is also derived from C. reticulata Blanco, can reduce the concentration of serum cytokines [interleukin-1 (IL-1), IL-6, tumor necrosis factor-α (TNFα)], enhance immunocompetence, produce beneficial effects on their nutritional status, and decrease the irradiation-induced inflammation in the radiation mouse group (Lee et al., 2011b). It exhibits anti-inflammatory activity by inhibiting the expression of hypoxia-inducible factor-1α, producing inflammatory cytokine from mast cells (Choi et al., 2007). Another example is that saponins from P. grandiflorus (Jacq.) A. DC could inhibit TNF-α-induced expression of adhesion molecules in human endothelial cells; stimulate the phosphorylation of endothelial nitric oxide synthase, and production of NO via the activation of PI3K/Akt, MAPK, AMPK, and Ca2 þ /calmodulin-dependent protein kinase II (Kim et al., 2010). Platycodin D, isolated from P. grandiflorus (Jacq.) A. DC, exerts a suppressive effect on the activation of NF-κB at the transcriptional level (Chung et al., 2008).
4. Clinical trials of phlegm-eliminating herbs for the treatment of cancer
6. Regulation of metabolic syndrome within the host
An increasing number of clinical studies have indicated that TCM could improve quality of life, prolong the survival time, reduce recurrence, metastasis, etc. in patients with cancer (Molassiotis et al., 2009).
The host's internal environment, as has been proven in some studies, also plays an important role in the occurrence of tumor and metastasis. The abnormal host environment, typified by metabolic syndrome (MS), has become the new focus in tumor
Please cite this article as: Xiu, L.-J., et al., Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties – An overview. Journal of Ethnopharmacology (2015), http://dx.doi.org/10.1016/j.jep.2015.05.032i
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biology in recent years. For example, studies suggest that MS, which includes symptoms such as obesity, hyperlipidemia, hyperglycemia, atherosclerosis, etc., is considered as a contributing factor to cancer as well as cardiovascular diseases (Halmos and Suba, 2008). In fact, it can be regarded as a high-risk state for particular tumors (Cowey and Hardy, 2006), raising the risk of cancer and thereafter affecting the relevant prognosis (Hursting and Berger, 2010; Legakis and Syrigos, 2010). On the other hand, the drugs designed to combat metabolic diseases such as metformin and simvastin can inhibit the tumor growth in xenografts which were injected with transformed non-cancerous immortalized breast cells (MCF-10A ER-Src cells) (Hirsch et al., 2010). Thus, MS is closely related to the occurrence, progression, and prognosis of cancer, although the specific mechanism remains unclear. Studies have suggested that the extracts or constituents of P. grandiflorus (Jacq.) A. DC (Park et al., 2007) and L. japonica Aresch (Huang et al., 2010) can reduce the plasma levels of triglyceride, total cholesterol, and low-density lipoprotein–cholesterol, and increase the plasma level of high-density lipoprotein–cholesterol in hyperlipidemic rats. Moreover, citrus limonoid from C. reticulata Blanco has been reported to have antiobesity and antihyperglycemic effects on mice fed on a high-fat diet (Ono et al., 2011). The powder of P. grandiflorus (Jacq.) A. DC can ameliorate obesity and insulin resistance, regulate lipid metabolism in obese mice via the activation of AMPK/ACC pathways and reduction of pancreatic lipase in vivo (Kim et al., 2000; Lee et al., 2012a). The antiobesity effects of saponins, the aqueous extract of P. grandiflorus (Jacq.) A. DC, may be due, in part, to the inhibition of intestinal absorption (Han et al., 2000). Further purification of active components yielded such triterpenoidal saponins as platycodin A, C, D, and deapioplatycodin D, which exhibited significant inhibitory effects on phospholipid in vitro (Xu et al., 2005).
7. Conclusion The relationships between cancer and other diseases such as inflammation and metabolic disease show the necessity for comprehensive treatment of cancer. The above-mentioned studies suggest that traditional Chinese phlegm-eliminating herbs and their active ingredients are effective in treating cancer by inducing apoptosis, anti-proliferation, preventing tumor invasion and metastasis, and reducing resistance to chemotherapy. In addition, phlegm-eliminating herbs and their active ingredients have antiinflammatory and anti-metabolic syndrome effects. Despite the fact that the phlegm-eliminating herbs and formulas are widely used to treat cancer patients in China, more controlled clinical research about them has yet to be conducted. We suggest that the phlegm-eliminating herbs and ingredients are potential candidates for anticancer treatment and cancer prevention by playing a comprehensive role.
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