Pharmaceutical Biology
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Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review Jia-Sui Zhang, Jie-Ping Lei, Guo-Qing Wei, Hui Chen, Chao-Ying Ma & HeZhong Jiang To cite this article: Jia-Sui Zhang, Jie-Ping Lei, Guo-Qing Wei, Hui Chen, Chao-Ying Ma & HeZhong Jiang (2016): Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review, Pharmaceutical Biology, DOI: 10.3109/13880209.2015.1113995 To link to this article: http://dx.doi.org/10.3109/13880209.2015.1113995
Published online: 10 Feb 2016.
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Date: 15 February 2016, At: 17:21
PHARMACEUTICAL BIOLOGY, 2016 http://dx.doi.org/10.3109/13880209.2015.1113995
REVIEW ARTICLE
Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review Jia-Sui Zhanga, Jie-Ping Leia, Guo-Qing Weia, Hui Chena, Chao-Ying Maa,b, and He-Zhong Jianga
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a School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China; bSchool of Medicine, Southwest Jiaotong University, Chengdu, China
ABSTRACT
ARTICLE HISTORY
Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004–2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.
Received 5 June 2015 Accepted 24 October 2015 Revised 2 September 2015 Published online 2 February 2016
Introduction Fatty acids are the major constituents of cellular membranes and play a pivotal role in energy homeostasis. When a cell is short of adenosine triphosphate (ATP), fatty acids are transformed into energy through b-oxidation. Fatty acid synthase (FAS), a multi-enzyme, catalyses the synthesis of fatty acids de novo. Fatty acids are mainly formed in the liver and some lipid tissues. The expression of FAS in these tissues is controlled by nutritional signals. The thyroid hormone, insulin and glucocorticoid can up-regulate the expression of FAS, while glucagon, cAMP, and unsaturated fatty acids can down-regulate the expression of FAS. However, most normal human cells prefer circulating free fatty acids from the diet, so the expression of FAS is low or undetectable (Menendez & Lupu 2004). Interestingly, the over-expression of FAS was significantly observed in many types of cancer, including prostate, breast, lung, ovary, bladder, stomach, oral cavity and melanoma (Carvalho et al. 2008). This can be explained by more lipids required from de novo synthesis, instead of getting the limited amount from blood CONTACT Dr. He-Zhong Jiang ! 2016 Taylor & Francis
[email protected]
KEYWORDS
Antitumour; mechanism of action; natural FAS inhibitors; phenolics
circulation for membrane and energy production in the proliferation of the cancer cell. Thus, the expression level of FAS was closely correlated with cancer progression, aggressiveness and metastasis (Murata et al. 2010). In carcinogenesis, FAS protects cancer cells from apoptosis by energy supply (Migita et al. 2009). These studies suggested that FAS is a potential target for anticancer drugs. In this review, we summarise the typically known natural FAS inhibitors and their possible mechanisms.
FAS structure Mammalian FAS is a 270 kDa cytosolic enzyme consisting of seven domains: b-ketoacyl synthase (KS), malonyl/ acetyl transferase (MAT), dehydrogenase (DH), enoyl reductase (ER), b-ketoacyl reductase (KR), acyl-carrier protein (ACP) and thioesterase (TE) (Zeng et al. 2011). FAS is the pivotal enzyme that catalyses de novo palmitic acid synthesis, using acetyl-CoA and malonylCoA as substrate. The synthesis starts with the acetylation of the KS active-site cysteine with ACP, which is recharged with a malonyl group from malonyl-CoA by the catalytic activity of MAT. Additionally, KS catalyses
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
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the condensation of malonyl-ACP with the acetyl moiety bound to KS. Then 3-oxo-acyl moiety is reduced, dehydrated, and further reduced by the successive action of KR, DH, and ER. Furthermore, this saturated acyl moiety, which has been elongated by two carbon atoms, serves as the substrate for a new round of elongation until the acyl chain is 16 carbon atoms in length. Finally, they are released from mFAS by TE (Pappenberger et al. 2010). A large number of FAS inhibitors have been reported, most of which can bind to the catalytic sites of the FAS enzyme. The tumour cells treated with FAS inhibitors are found to apoptosise both in vitro and in vivo. The level of FAS is suggested to play a causal role in tumourigenesis (Pandey et al. 2011). However, the exact mechanism of the inhibition of FAS leading to apoptosis in tumour cells is still unclear.
Known FAS inhibitors Orlistat
C75 and C93 C75 (3), the synthetic derivative of cerulenin, is a more stable compound. C75 acts on KR, ACP and TE domains of FAS as a competitive irreversible inhibitor. Additionally, C75 has little side effects compared to cerulenin, but except anorexia and weight loss, by activating CPT1 to accelerate fatty acid b-oxidation. Furthermore, it is a common reference substance of FAS inhibitor with the IC50 value at 200 mg/mL (Pandey et al. 2012). C93, the second generation of synthetic FAS inhibitors, and an upgrade of C75 to improve the side effects, inhibits FAS by binding irreversibly to KS domain, similar to cerulenin and C75 (McFadden et al. 2005).
FAS inhibitors in plants
Orlistat (1), an anti-obesity drug approved by Food and Drug Administration (FDA) of USA, prevents the absorption of fats by inhibiting pancreatic lipase, which can break down triglycerides in the intestine to decrease the caloric intake (Pandey et al. 2012) (Figure 1). Orlistat has been reported as a potent inhibitor of FAS with an IC50 value of 0.9 mM, mainly irreversibly acts on TE domain of FAS. In the treatment of obesity, orlistat down-regulates DNA synthesis to suppress cell proliferation at the G1/S stage (Pandey et al. 2012). Furthermore, orlistat induces tumour apoptosis by activating caspase-8 (Knowles et al. 2008).
Cerulenin (2), isolated from the fungi Cephalosporium caerulens, is a promising FAS inhibitor, which irreversibly binds to KS domain of FAS. The cytotoxicity of cerulenin is found to have connection with the accumulation of malonyl-CoA. The high level of malonyl-CoA O
O NH2
O 2 O
OO H 1
Due to the unselective cytotoxicity and the side effects of cerulenin and C75, there is an increasing interest in the natural effective FAS inhibitors from plants. Many plants have been investigated, and their active ingredients, such as phenolics, are identified to inhibit the FAS. Phenolics The FAS inhibitory phenolic constituents, distributed widely in plants, particularly, with the conjugated system of phenyl and carbonyl, have been reported. Catechins
Cerulenin
O
may induce the apoptosis by inhibiting CPT1, which leads to the up-regulation of ceramide and activation of a set of genes BNIP3, TRAIL and DAPK2 (Pandey et al. 2012).
N H
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Figure 1. The structures of orlistat (1), cerulrnin (2) and C75 (3).
Tea is known for its antioxidant properties, and is considered as a healthy drink by the World Health Organization (WHO). The tea polyphenols, such as catechins, flavones, theaflavins, are reported to inhibit the expression of FAS. The 30–40% of polyphenols of green tea decrease the risk of cancer (Zeng et al. 2013), by mainly acting on KS, KR, and TE domain of FAS (Tian 2006). Catechins are the main bioactive ingredients of green tea, among which ( )-epigallocatechin-3gallate (EGCG) (4) is the richest one and has a number of physiological activities (Figure 2). The IC50 value of FAS inhibition by EGCG is 42.0 mg/mL. EGCG inhibits adipocyte viability in a dose- and time-dependent manner, and terminates cell cycle at G0/G1 phase (Wang et al. 2014). EGCG exhibits both reversible fastbinding and irreversible slow-binding inhibition of FAS, mainly on the KR domain (Ilze et al. 2011). Furthermore,
PHARMACEUTICAL BIOLOGY OH
OH
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O
OH HO
O
OH OH
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HO HO
O O
OH
OH
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O OH H3CO OH HO
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O
OH
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O
OH O
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O
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H H 9
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Figure 2. The structures of egcg (4), amentoflavone (5), -mangostin (6), -mangostin (7), cacalol (8), and diosgenin (9).
all the esterified catechins inhibit FAS by competing with NADPH to the binding-site of FAS (Pandey et al. 2012). Among tea polyphenols, EGCG possesses the most potent anticancer activity on human colorectal cancer cells. The cell cycle arrest and apoptosis induction might be the mechanism (Du et al. 2012). Additionally, EGCG induces cancer cells apoptosis and causes a marked decrease in the levels of activated HER2, AKT and ERK1/2 proteins. The above-mentioned data support the model of MAPK and PI3K/AKT activation up-regulate FAS expression in breast, colon, ovarian and prostate cancer cells (Ilze et al. 2011). EGCG has the comparable effect as C75 in inhibiting cancer cells, without inducing CPT activity, hence avoided C75 side effects (Terasa et al. 2008). The toxicity of EGCG seems to be the reason for liver damage (Joana et al. 2012). Epicatechin gallate (ECG) has inhibitory mechanism similar to FAS on EGCG with an IC50 value of 30.1 mg/ mL. Catechin gallate (CG), the optical isomer of ECG, acts weakly on KR domain of FAS and is a more potent inhibitor than EGCG with the IC50 of 1.5 mg/mL. CG mainly inhibits FAS by competing with acetyl-CoA. However, epicatechin (EC) and catechin do not show the irreversibly inhibition of FAS. Theaflavin, from black tea, has stronger inhibitory activity (IC50 1.2 mg/mL) on FAS than EGCG. It shows both reversible fast-binding and irreversible slow-binding inhibition of FAS on the KR domain (Tian 2006).
Extra-virgin olive oil (EVOO)-derived phenolics EVOO-derived phenolics (lignans, secoiridoids, and flavonoids), by blockading the HER2 tyrosine kinase effects (Menendez et al. 2007), drastically suppress the expression of FAS protein in HER2 over-expressing breast cancer cells (Menendez et al. 2008). In addition,
EVOO-derived phenolics are more effective than the mono-HER2 inhibitor trastuzumab, while the single phenolic component failed to modulate FAS expression (Menendez et al. 2008).
Flavonoids Flavonoids are widely distributed in plants. The extracts of parasitic loranthus, polygonum multiforum, galangal, night kodo, maple leaf, containing flavonoids, are reported to inhibit FAS (Tian et al. 2011). In addition, the extracts of Citrus reticulate Blanco (Rutaceae) and Canarium album Raeuseh (Burseraceae) leaves, containing the flavonoids, have better inhibitory effect on FAS compared to C75 (Chen et al. 2009). Luteolin, from many edible plants, has a similar structure as PI3K inhibitors and inhibits FAS with an IC50 value of 2.5 mg/mL. PI3K is the upstream of FAS that reduces the amount and the enzymatic activity of FAS (Pandey et al. 2012). Luteolin down-regulates the FLP expression by inactivating Akt and STAT3, and sensitising human renal cell carcinoma cells to TRAILinduced apoptosis (Ou et al. 2014). In addition, luteolin is effective in stringently controlling glucose entry and anaplerosis in the TCA cycle, by which it promotes less cholesterol synthesis than does C75. Luteolin is considered as a non-toxic natural treatment modality for pancreatic cancer (Harris et al. 2012). Quercetin is widely distributed in plants, such as apples, lovage and tea, and shows strong and reversible inhibition on FAS, targeting mainly on MAT domain. In addition, quercetin controls tumour proliferation by inhibiting glycogen synthesis and turnover (Harris et al. 2012), with an IC50 value of 17.1 mg/mL (Bitencourt et al. 2013). Moreover, quercetin exhibits synergistic effects with cisplatin against nasopharyngeal carcinoma cells,
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which could reduce the risk of cisplatin-associated toxicity (Daker et al. 2012). However, the poor solubility in water restricts its use (Aras et al. 2014). Amentoflavone (5) is effective in inhibiting FAS expression in HER2-positive SKBR3 cells, in which it specifically down-regulates HER2 protein as well as mRNA, suppresses HER2 activation, modulates Akt, mTOR, and JNK phosphorylation, and decreases cell viability and induces cell death (Lee et al. 2013).
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Tannins Tannins are water-soluble polyphenols and existed widely in plants. It is surprisingly to find that tannins (both condensed and hydrolysable tannins, which was used to be considered as useless constitute need to be removed) can inhibit FAS strongly. The condensed tannins mainly act on MAT domain of FAS. The trimeric condensed tannins inhibit b-ketoacyl reduction reaction of FAS by competing with NADPH with an IC50 value of 0.65 mM (Tian et al. 2011). The genus Geum (Rosaceae) are known to be rich in tannins. Several hydrolysable tannins and triterpenoid acids, such as ellagitannins, casuarinin, gemin G, gemin A, pedunculagin, potentillin and ellagic acid, which were isolated from Geum japonicum Thunb. var. chinense F. Bolle (Rosaceae), exhibit strong inhibitory activity against FAS with IC50 values at the range of 0.21–41.4 mM (Liu et al. 2009).
Other phenols Ginkgolic acid derivatives, isolated from Ginkgo biloba L. (Ginkgoaceae), inhibit the expression of FAS, which suggested alkylphenol derivatives a new type of FAS inhibitor (Oh et al. 2013). The a-mangostin (6) and g-mangostin (7), two xanthones isolated from the fruit hull of Garcinia mangostana L. (Clusiaceae), showed significant inhibitory activities against FAS with IC50 values of 5.54 and 1.24 mM, respectively (Jiang et al. 2010). In addition, a-mangostin mainly acted on the KS domain and weakly on the MAT domain (Quan et al. 2012). This result suggested that xanthones as another promising class of FAS inhibitors. Curcumin is a well-known component of Curcuma longa L. (Zingiberaceae), and an effective inhibitor of FAS. In HepG2 cell, curcumin causes apoptosis by inhibiting the expression and mRNA level of FAS with an IC50 value of 8.8 mg/mL (Fan et al. 2014). Curcumin shows both fast-binding and slow-binding inhibitions to FAS, inhibits FAS non-competitively with NADPH and partial-competitively with both acetyl-CoA and malonylCoA. This suggests that the MAT domain is potentially the main target of curcumin (Zhao et al. 2011). Furthermore, curcumin is a promising cancer chemotherapeutic agents because of its low toxicity (Oyagbemi et al. 2009).
Terpenoids Stilbenes A stilbene glucoside, isolated from traditional Chinese herb Fallopia multiflora (Thunb.) Harald, was reported to inhibit the FAS expression (Liang et al. 2009). Resveratrol, rich in the peels and seeds of grapes, inhibits FAS reversibly on KR domain with an IC50 value of 6.1 mg/mL (Tian et al. 2011). It has competitive inhibition with acetylCoA, non-competitive inhibition with malonyl-CoA and in a mixed manner with NADPH (Liang et al. 2013). In a xenograft model of breast cancer, resveratrol suppresses the cell growth by inhibiting FAS expression and inducing the pro-apoptotic signalling pathway (Pandey et al. 2011). In addition, resveratrol causes cytotoxicity to cancer cells for a saturated fatty acid context primarily by inhibiting triglyceride accumulation, probably leading to an intracellular palmitate accumulation that induces cancer cells death (Rojas et al. 2014). Moreover, resveratrol is considered as a promising radiosensitising agent that enhances radiation sensitivity in PCA to control cancer, by inhibiting cell proliferation and promoting cell senescence and apoptosis in vitro (Kma 2013). Today, resveratrol are manufactured as health care products.
Cacalol (8) is a sesquiterpene derivative isolated from many medicinal plants, for example, Ligularia tsangchanensis (Asteraceae) (Torihata et al. 2007) and Psacalium Decompositum (Asteraceae) (Jimenez-Estrada et al. 2006). This compound suppresses SREBP1, a major transcription regulator of FAS, by blocking PI3K/Akt signal (.Liu et al. 2011). Furthermore, cacalol inhibits FAS specifically without affecting other downstream targets of SREBP1 pathway (Pandey et al. 2012). However, it shows a noticeable toxicity in animals (Pandey et al. 2012). Ursolic acid and oleanolic acid, two triterpenoids, are widely distributed in fruits. Ursolic acid strongly inhibits FAS with an IC50 value of 6 mg/mL, acting mainly on the MAT domain and weakly on the KS domain (Tian et al. 2011). Ursolic acid reduces the free radical and restores the membrane integrity (Gayathri et al. 2009). In addition, the oleanane-type triterpene and its oligoglycosides isolated from the hulls of Nephelium lappaceum L. (Sapindaceae) showed effective FAS inhibitions with IC50 values ranging from 34.5 to 204.4 mM (Jiang et al. 2012).
PHARMACEUTICAL BIOLOGY
Steroidal sapogenin Diosgenin (9), a member of steroidal sapogenin, distributed in Solanum (Solanaceae) and Dioscorea (Dioscoreaceae) species, has shown effects on lipid metabolism and property of anti-tumour (Shishodia & Aggarwal 2006). It downregulates FAS expression, inhibits proliferation and induces apoptosis in HER2 over-expressing cancer cells, by modulating Akt, mTOR and JNK phosphorylation (Chiang et al. 2007).
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Other structures Soy peptides are isolated from hydrolysates of purified b-conglycinin: KNPQLR, EITPEKNPQLR and RKQEE DEDEEQQRE with inhibitory activity against FAS expression. These peptides bond to the TE domain of human FAS with lower interaction energies than classical TE inhibitors. The IC50 values of EITPEKNPQLR and RKQEEDEDEEQQRE are 10.1 and 10.7 mM, respectively, higher than C75 (IC50, 58.7 mM) but lower than Orlistat (IC50, 0.9 mM) (Martinez-Villaluenga et al. 2010).
Discussion The over-expression of FAS can be observed in most tumours. The inhibition of the FAS expression results in tumour apoptosis. Thus, FAS is considered as a promising target for drug discovery. The currently available FAS inhibitors, for example, cerulenin, C75 and orlistat, are relatively unstable and have side effects, such as weight loss and anorexia. Furthermore, these inhibitors activate the CPT-1, and aggravate fatty acid oxidation in mitochondrial (Pizer et al. 2000). Therefore, the use of these inhibitors is limited. Natural FAS inhibitors are widely distributed in plants, and these natural products have shown potent inhibition, but less toxicity, and hold promise in the development for effective and inexpensive therapeutics.
Disclosure statement The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Funding information This work was supported by the National Natural Science Foundation of China (NSFC) (No. 31200256), the Science and Technology Support Program of Sichuan Province (2014SZ0071), the Fundamental Research
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Funds for the Central Universities (2682014CX045), and the Foundation of Science and Technology Agency of Chengdu (12DXYB228JH-002).
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ISSN: 1388-0209 (Print) 1744-5116 (Online) Journal homepage: http://www.tandfonline.com/loi/iphb20
Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review Jia-Sui Zhang, Jie-Ping Lei, Guo-Qing Wei, Hui Chen, Chao-Ying Ma & HeZhong Jiang To cite this article: Jia-Sui Zhang, Jie-Ping Lei, Guo-Qing Wei, Hui Chen, Chao-Ying Ma & HeZhong Jiang (2016): Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review, Pharmaceutical Biology, DOI: 10.3109/13880209.2015.1113995 To link to this article: http://dx.doi.org/10.3109/13880209.2015.1113995
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PHARMACEUTICAL BIOLOGY, 2016 http://dx.doi.org/10.3109/13880209.2015.1113995
REVIEW ARTICLE
Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review Jia-Sui Zhanga, Jie-Ping Leia, Guo-Qing Weia, Hui Chena, Chao-Ying Maa,b, and He-Zhong Jianga
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a School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China; bSchool of Medicine, Southwest Jiaotong University, Chengdu, China
ABSTRACT
ARTICLE HISTORY
Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004–2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.
Received 5 June 2015 Accepted 24 October 2015 Revised 2 September 2015 Published online 2 February 2016
Introduction Fatty acids are the major constituents of cellular membranes and play a pivotal role in energy homeostasis. When a cell is short of adenosine triphosphate (ATP), fatty acids are transformed into energy through b-oxidation. Fatty acid synthase (FAS), a multi-enzyme, catalyses the synthesis of fatty acids de novo. Fatty acids are mainly formed in the liver and some lipid tissues. The expression of FAS in these tissues is controlled by nutritional signals. The thyroid hormone, insulin and glucocorticoid can up-regulate the expression of FAS, while glucagon, cAMP, and unsaturated fatty acids can down-regulate the expression of FAS. However, most normal human cells prefer circulating free fatty acids from the diet, so the expression of FAS is low or undetectable (Menendez & Lupu 2004). Interestingly, the over-expression of FAS was significantly observed in many types of cancer, including prostate, breast, lung, ovary, bladder, stomach, oral cavity and melanoma (Carvalho et al. 2008). This can be explained by more lipids required from de novo synthesis, instead of getting the limited amount from blood CONTACT Dr. He-Zhong Jiang ! 2016 Taylor & Francis
[email protected]
KEYWORDS
Antitumour; mechanism of action; natural FAS inhibitors; phenolics
circulation for membrane and energy production in the proliferation of the cancer cell. Thus, the expression level of FAS was closely correlated with cancer progression, aggressiveness and metastasis (Murata et al. 2010). In carcinogenesis, FAS protects cancer cells from apoptosis by energy supply (Migita et al. 2009). These studies suggested that FAS is a potential target for anticancer drugs. In this review, we summarise the typically known natural FAS inhibitors and their possible mechanisms.
FAS structure Mammalian FAS is a 270 kDa cytosolic enzyme consisting of seven domains: b-ketoacyl synthase (KS), malonyl/ acetyl transferase (MAT), dehydrogenase (DH), enoyl reductase (ER), b-ketoacyl reductase (KR), acyl-carrier protein (ACP) and thioesterase (TE) (Zeng et al. 2011). FAS is the pivotal enzyme that catalyses de novo palmitic acid synthesis, using acetyl-CoA and malonylCoA as substrate. The synthesis starts with the acetylation of the KS active-site cysteine with ACP, which is recharged with a malonyl group from malonyl-CoA by the catalytic activity of MAT. Additionally, KS catalyses
School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, China
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the condensation of malonyl-ACP with the acetyl moiety bound to KS. Then 3-oxo-acyl moiety is reduced, dehydrated, and further reduced by the successive action of KR, DH, and ER. Furthermore, this saturated acyl moiety, which has been elongated by two carbon atoms, serves as the substrate for a new round of elongation until the acyl chain is 16 carbon atoms in length. Finally, they are released from mFAS by TE (Pappenberger et al. 2010). A large number of FAS inhibitors have been reported, most of which can bind to the catalytic sites of the FAS enzyme. The tumour cells treated with FAS inhibitors are found to apoptosise both in vitro and in vivo. The level of FAS is suggested to play a causal role in tumourigenesis (Pandey et al. 2011). However, the exact mechanism of the inhibition of FAS leading to apoptosis in tumour cells is still unclear.
Known FAS inhibitors Orlistat
C75 and C93 C75 (3), the synthetic derivative of cerulenin, is a more stable compound. C75 acts on KR, ACP and TE domains of FAS as a competitive irreversible inhibitor. Additionally, C75 has little side effects compared to cerulenin, but except anorexia and weight loss, by activating CPT1 to accelerate fatty acid b-oxidation. Furthermore, it is a common reference substance of FAS inhibitor with the IC50 value at 200 mg/mL (Pandey et al. 2012). C93, the second generation of synthetic FAS inhibitors, and an upgrade of C75 to improve the side effects, inhibits FAS by binding irreversibly to KS domain, similar to cerulenin and C75 (McFadden et al. 2005).
FAS inhibitors in plants
Orlistat (1), an anti-obesity drug approved by Food and Drug Administration (FDA) of USA, prevents the absorption of fats by inhibiting pancreatic lipase, which can break down triglycerides in the intestine to decrease the caloric intake (Pandey et al. 2012) (Figure 1). Orlistat has been reported as a potent inhibitor of FAS with an IC50 value of 0.9 mM, mainly irreversibly acts on TE domain of FAS. In the treatment of obesity, orlistat down-regulates DNA synthesis to suppress cell proliferation at the G1/S stage (Pandey et al. 2012). Furthermore, orlistat induces tumour apoptosis by activating caspase-8 (Knowles et al. 2008).
Cerulenin (2), isolated from the fungi Cephalosporium caerulens, is a promising FAS inhibitor, which irreversibly binds to KS domain of FAS. The cytotoxicity of cerulenin is found to have connection with the accumulation of malonyl-CoA. The high level of malonyl-CoA O
O NH2
O 2 O
OO H 1
Due to the unselective cytotoxicity and the side effects of cerulenin and C75, there is an increasing interest in the natural effective FAS inhibitors from plants. Many plants have been investigated, and their active ingredients, such as phenolics, are identified to inhibit the FAS. Phenolics The FAS inhibitory phenolic constituents, distributed widely in plants, particularly, with the conjugated system of phenyl and carbonyl, have been reported. Catechins
Cerulenin
O
may induce the apoptosis by inhibiting CPT1, which leads to the up-regulation of ceramide and activation of a set of genes BNIP3, TRAIL and DAPK2 (Pandey et al. 2012).
N H
O
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HO O 3
Figure 1. The structures of orlistat (1), cerulrnin (2) and C75 (3).
Tea is known for its antioxidant properties, and is considered as a healthy drink by the World Health Organization (WHO). The tea polyphenols, such as catechins, flavones, theaflavins, are reported to inhibit the expression of FAS. The 30–40% of polyphenols of green tea decrease the risk of cancer (Zeng et al. 2013), by mainly acting on KS, KR, and TE domain of FAS (Tian 2006). Catechins are the main bioactive ingredients of green tea, among which ( )-epigallocatechin-3gallate (EGCG) (4) is the richest one and has a number of physiological activities (Figure 2). The IC50 value of FAS inhibition by EGCG is 42.0 mg/mL. EGCG inhibits adipocyte viability in a dose- and time-dependent manner, and terminates cell cycle at G0/G1 phase (Wang et al. 2014). EGCG exhibits both reversible fastbinding and irreversible slow-binding inhibition of FAS, mainly on the KR domain (Ilze et al. 2011). Furthermore,
PHARMACEUTICAL BIOLOGY OH
OH
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O
OH HO
O
OH OH
O
HO HO
O O
OH
OH
O
OH
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O OH H3CO OH HO
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O
OH
O
OH
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OH
O
OH O
H
O
OH
H
HO H HO
O
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HO
O
H H 9
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Figure 2. The structures of egcg (4), amentoflavone (5), -mangostin (6), -mangostin (7), cacalol (8), and diosgenin (9).
all the esterified catechins inhibit FAS by competing with NADPH to the binding-site of FAS (Pandey et al. 2012). Among tea polyphenols, EGCG possesses the most potent anticancer activity on human colorectal cancer cells. The cell cycle arrest and apoptosis induction might be the mechanism (Du et al. 2012). Additionally, EGCG induces cancer cells apoptosis and causes a marked decrease in the levels of activated HER2, AKT and ERK1/2 proteins. The above-mentioned data support the model of MAPK and PI3K/AKT activation up-regulate FAS expression in breast, colon, ovarian and prostate cancer cells (Ilze et al. 2011). EGCG has the comparable effect as C75 in inhibiting cancer cells, without inducing CPT activity, hence avoided C75 side effects (Terasa et al. 2008). The toxicity of EGCG seems to be the reason for liver damage (Joana et al. 2012). Epicatechin gallate (ECG) has inhibitory mechanism similar to FAS on EGCG with an IC50 value of 30.1 mg/ mL. Catechin gallate (CG), the optical isomer of ECG, acts weakly on KR domain of FAS and is a more potent inhibitor than EGCG with the IC50 of 1.5 mg/mL. CG mainly inhibits FAS by competing with acetyl-CoA. However, epicatechin (EC) and catechin do not show the irreversibly inhibition of FAS. Theaflavin, from black tea, has stronger inhibitory activity (IC50 1.2 mg/mL) on FAS than EGCG. It shows both reversible fast-binding and irreversible slow-binding inhibition of FAS on the KR domain (Tian 2006).
Extra-virgin olive oil (EVOO)-derived phenolics EVOO-derived phenolics (lignans, secoiridoids, and flavonoids), by blockading the HER2 tyrosine kinase effects (Menendez et al. 2007), drastically suppress the expression of FAS protein in HER2 over-expressing breast cancer cells (Menendez et al. 2008). In addition,
EVOO-derived phenolics are more effective than the mono-HER2 inhibitor trastuzumab, while the single phenolic component failed to modulate FAS expression (Menendez et al. 2008).
Flavonoids Flavonoids are widely distributed in plants. The extracts of parasitic loranthus, polygonum multiforum, galangal, night kodo, maple leaf, containing flavonoids, are reported to inhibit FAS (Tian et al. 2011). In addition, the extracts of Citrus reticulate Blanco (Rutaceae) and Canarium album Raeuseh (Burseraceae) leaves, containing the flavonoids, have better inhibitory effect on FAS compared to C75 (Chen et al. 2009). Luteolin, from many edible plants, has a similar structure as PI3K inhibitors and inhibits FAS with an IC50 value of 2.5 mg/mL. PI3K is the upstream of FAS that reduces the amount and the enzymatic activity of FAS (Pandey et al. 2012). Luteolin down-regulates the FLP expression by inactivating Akt and STAT3, and sensitising human renal cell carcinoma cells to TRAILinduced apoptosis (Ou et al. 2014). In addition, luteolin is effective in stringently controlling glucose entry and anaplerosis in the TCA cycle, by which it promotes less cholesterol synthesis than does C75. Luteolin is considered as a non-toxic natural treatment modality for pancreatic cancer (Harris et al. 2012). Quercetin is widely distributed in plants, such as apples, lovage and tea, and shows strong and reversible inhibition on FAS, targeting mainly on MAT domain. In addition, quercetin controls tumour proliferation by inhibiting glycogen synthesis and turnover (Harris et al. 2012), with an IC50 value of 17.1 mg/mL (Bitencourt et al. 2013). Moreover, quercetin exhibits synergistic effects with cisplatin against nasopharyngeal carcinoma cells,
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which could reduce the risk of cisplatin-associated toxicity (Daker et al. 2012). However, the poor solubility in water restricts its use (Aras et al. 2014). Amentoflavone (5) is effective in inhibiting FAS expression in HER2-positive SKBR3 cells, in which it specifically down-regulates HER2 protein as well as mRNA, suppresses HER2 activation, modulates Akt, mTOR, and JNK phosphorylation, and decreases cell viability and induces cell death (Lee et al. 2013).
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Tannins Tannins are water-soluble polyphenols and existed widely in plants. It is surprisingly to find that tannins (both condensed and hydrolysable tannins, which was used to be considered as useless constitute need to be removed) can inhibit FAS strongly. The condensed tannins mainly act on MAT domain of FAS. The trimeric condensed tannins inhibit b-ketoacyl reduction reaction of FAS by competing with NADPH with an IC50 value of 0.65 mM (Tian et al. 2011). The genus Geum (Rosaceae) are known to be rich in tannins. Several hydrolysable tannins and triterpenoid acids, such as ellagitannins, casuarinin, gemin G, gemin A, pedunculagin, potentillin and ellagic acid, which were isolated from Geum japonicum Thunb. var. chinense F. Bolle (Rosaceae), exhibit strong inhibitory activity against FAS with IC50 values at the range of 0.21–41.4 mM (Liu et al. 2009).
Other phenols Ginkgolic acid derivatives, isolated from Ginkgo biloba L. (Ginkgoaceae), inhibit the expression of FAS, which suggested alkylphenol derivatives a new type of FAS inhibitor (Oh et al. 2013). The a-mangostin (6) and g-mangostin (7), two xanthones isolated from the fruit hull of Garcinia mangostana L. (Clusiaceae), showed significant inhibitory activities against FAS with IC50 values of 5.54 and 1.24 mM, respectively (Jiang et al. 2010). In addition, a-mangostin mainly acted on the KS domain and weakly on the MAT domain (Quan et al. 2012). This result suggested that xanthones as another promising class of FAS inhibitors. Curcumin is a well-known component of Curcuma longa L. (Zingiberaceae), and an effective inhibitor of FAS. In HepG2 cell, curcumin causes apoptosis by inhibiting the expression and mRNA level of FAS with an IC50 value of 8.8 mg/mL (Fan et al. 2014). Curcumin shows both fast-binding and slow-binding inhibitions to FAS, inhibits FAS non-competitively with NADPH and partial-competitively with both acetyl-CoA and malonylCoA. This suggests that the MAT domain is potentially the main target of curcumin (Zhao et al. 2011). Furthermore, curcumin is a promising cancer chemotherapeutic agents because of its low toxicity (Oyagbemi et al. 2009).
Terpenoids Stilbenes A stilbene glucoside, isolated from traditional Chinese herb Fallopia multiflora (Thunb.) Harald, was reported to inhibit the FAS expression (Liang et al. 2009). Resveratrol, rich in the peels and seeds of grapes, inhibits FAS reversibly on KR domain with an IC50 value of 6.1 mg/mL (Tian et al. 2011). It has competitive inhibition with acetylCoA, non-competitive inhibition with malonyl-CoA and in a mixed manner with NADPH (Liang et al. 2013). In a xenograft model of breast cancer, resveratrol suppresses the cell growth by inhibiting FAS expression and inducing the pro-apoptotic signalling pathway (Pandey et al. 2011). In addition, resveratrol causes cytotoxicity to cancer cells for a saturated fatty acid context primarily by inhibiting triglyceride accumulation, probably leading to an intracellular palmitate accumulation that induces cancer cells death (Rojas et al. 2014). Moreover, resveratrol is considered as a promising radiosensitising agent that enhances radiation sensitivity in PCA to control cancer, by inhibiting cell proliferation and promoting cell senescence and apoptosis in vitro (Kma 2013). Today, resveratrol are manufactured as health care products.
Cacalol (8) is a sesquiterpene derivative isolated from many medicinal plants, for example, Ligularia tsangchanensis (Asteraceae) (Torihata et al. 2007) and Psacalium Decompositum (Asteraceae) (Jimenez-Estrada et al. 2006). This compound suppresses SREBP1, a major transcription regulator of FAS, by blocking PI3K/Akt signal (.Liu et al. 2011). Furthermore, cacalol inhibits FAS specifically without affecting other downstream targets of SREBP1 pathway (Pandey et al. 2012). However, it shows a noticeable toxicity in animals (Pandey et al. 2012). Ursolic acid and oleanolic acid, two triterpenoids, are widely distributed in fruits. Ursolic acid strongly inhibits FAS with an IC50 value of 6 mg/mL, acting mainly on the MAT domain and weakly on the KS domain (Tian et al. 2011). Ursolic acid reduces the free radical and restores the membrane integrity (Gayathri et al. 2009). In addition, the oleanane-type triterpene and its oligoglycosides isolated from the hulls of Nephelium lappaceum L. (Sapindaceae) showed effective FAS inhibitions with IC50 values ranging from 34.5 to 204.4 mM (Jiang et al. 2012).
PHARMACEUTICAL BIOLOGY
Steroidal sapogenin Diosgenin (9), a member of steroidal sapogenin, distributed in Solanum (Solanaceae) and Dioscorea (Dioscoreaceae) species, has shown effects on lipid metabolism and property of anti-tumour (Shishodia & Aggarwal 2006). It downregulates FAS expression, inhibits proliferation and induces apoptosis in HER2 over-expressing cancer cells, by modulating Akt, mTOR and JNK phosphorylation (Chiang et al. 2007).
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Other structures Soy peptides are isolated from hydrolysates of purified b-conglycinin: KNPQLR, EITPEKNPQLR and RKQEE DEDEEQQRE with inhibitory activity against FAS expression. These peptides bond to the TE domain of human FAS with lower interaction energies than classical TE inhibitors. The IC50 values of EITPEKNPQLR and RKQEEDEDEEQQRE are 10.1 and 10.7 mM, respectively, higher than C75 (IC50, 58.7 mM) but lower than Orlistat (IC50, 0.9 mM) (Martinez-Villaluenga et al. 2010).
Discussion The over-expression of FAS can be observed in most tumours. The inhibition of the FAS expression results in tumour apoptosis. Thus, FAS is considered as a promising target for drug discovery. The currently available FAS inhibitors, for example, cerulenin, C75 and orlistat, are relatively unstable and have side effects, such as weight loss and anorexia. Furthermore, these inhibitors activate the CPT-1, and aggravate fatty acid oxidation in mitochondrial (Pizer et al. 2000). Therefore, the use of these inhibitors is limited. Natural FAS inhibitors are widely distributed in plants, and these natural products have shown potent inhibition, but less toxicity, and hold promise in the development for effective and inexpensive therapeutics.
Disclosure statement The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
Funding information This work was supported by the National Natural Science Foundation of China (NSFC) (No. 31200256), the Science and Technology Support Program of Sichuan Province (2014SZ0071), the Fundamental Research
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Funds for the Central Universities (2682014CX045), and the Foundation of Science and Technology Agency of Chengdu (12DXYB228JH-002).
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