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Indian Journal of Cancer, Vol. 47, No. 1, January-March, 2010, pp. 53-58 Review Article Capsaicin: A novel chemopreventive molecule and its underlying molecular mechanisms of action Oyagbemi AA, Saba AB, Azeez OI Department of Veterinary Physiology, Biochemistry and Pharmacology, Faculty of Veterinary Medicine, University of Ibadan, Oyo State, Nigeria Code Number: cn10012 PMID: 20071791 DOI: 10.4103/0019-509X.58860 Abstract Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the a principal pungent ingredient of hot red and chili peppers that belong to the plant genus Capsicum (Solanaceae). Capsaicin is a cancer-suppressing agent. It blocks the translocation of nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT3) signaling pathway that are required for carcinogenesis. The anti-inflammatory potential of capsaicin is attributed to its inhibitory effect on inducible COX-2 mRNA expression. Cytochrome P4502E1 mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites. This metabolic activation of xenobiotics by Cytochrome P4502E1 has been shown to be inhibited by capsaicin. Capsaicin also generates reactive oxygen species in cells with resultant induction of apoptosis and cell cycle arrest, which is beneficial for cancer chemoprevention. Therefore, the use of capsaicin as a chemopreventive agent is of immense benefit for cancer chemoprevention. The search strategy included printed journals, pubmed, and medline, using the terms 'capsaicin' and 'anticancer' citations, relevant to anticancer properties of capsaicin.Keywords: Capsaicin, cancer chemoprevention, COX-2, NF-kB, Ap-1, Stat3 Introduction Capsaicin (trans-8-methyl-N-Vanilyl-6-nonenamide) is the pungent ingredient found in red pepper and hot chili pepper. [1] It has principally been used as spice, food additive, as drugs. [2],[3],[4] Capsaicin belongs to the plant genus Capsicum of family Solanaceae. The effects of capsaicin on multistage carcinogenesis and mutagenesis has been extensively experimented and discussed. [5],[6],[7],[8] Capsaicin is metabolized mainly by liver CYP 450 and carboxyesterases to a wide array of O-demethylated, hydroxylated, and N-dehydrogenated products. [5],[8] Capsaicin was suggested to generate potentially toxic reactive intermediates during its metabolism; these reactive intermediates include epoxides, quinones, and phenoxy radicals, which are reported to act as suicide inhibitors of CYP2E1. [5],[8] One-electron reduction of capsaicin specifically plays a role in capsaicin metabolism. Pharmacologically, capsaicin has been documented to modulate microsomal cytochrome P450-dependent monooxygenase activities with resultant alteration of metabolism of carcinogen and other xenobiotics, to ultimate carcinogen. [8],[9],[10] Pulmonary tumours Pulmonary s induced by benzo(a)pyrene are inhibited by capsaicin with significant inhibitory effects on mutagenecity and/or covalent DNA binding of aflatoxin B 1 and tobacco-specific nitrosamine 4-(metaylntrosamino)-1-(3-pyridyl)-1-batanone (NNK). [11] However, Cytochrome P4502E1, which mediates the activation of xenobiotics such as vinyl carbamate and dimethyl nitrosamine to their toxic metabolites, has been shown to be inhibited by capsaicin. [12],[13] The methods of literature search for this review article include pubmed, medline, and printed journal articles. Beneficial Effects of Capsaicin on Peptic Ulcer Capsaicin is found to have gastroprotective effect against experimental gastric injury when given intragastrically. Previous epidemiological and clinical data suggested that chilli ingestion may have a beneficial effect on human peptic ulcer disease. [14] Increased gastric mucus production has been suggested as one mechanism by which capsaicin and chilli exert their gastroprotective effect, and reduction in mucosal mucus depletion which has been found to act as secondary protective effect of capsaicin and chilli. [14] However, -sensitive afferent neurons have been to participate in gastric mucosal protection against ulcerogenic factors. [15] Stimulation of afferent neurons by intragastric capsaicin was therefore suggested to offer protection of the experimental animals against ethanol-induced gastric mucosa damage. [15] Molecular Mechanisms Associated with Capsaicin Anticancer Activities A number of phytochemicals present in medicinal plants are known to possess substantial anti-carcinogenic and anti-mutagenic activities. [16],[17] Capsaicin is a known phytochemical that preferentially repress the growth of various immortalized or malignant cell lines via induction of apoptosis. [18],[19] Keisuke et al. also reported the suppression or growth of leukemic cells via induction of cycle arrest at G 0 -G 1 phase and apoptosis. [20] Induction of apoptosis is in association with significant elevation of intracellular reactive oxygen species (ROS) production in cells. Cellular proliferation is known to play a major role in multistage carcinogenesis with associated multiple genetic alterations, hence, cell proliferation is a hallmark of cancer prevention. [21],[22] Therefore, inhibitory effects of capsaicin on cancer development in multiple organs, such as, stomach, lung, and liver have been extensively documented. [5],[22].[23] These inhibitory effects of capsaicin on promoter through the inactivation of two defined eukaryotic transcription factors, nuclear factor-kappa β (NF-kB), and activator protein 1 (AP-1) have been reported. [7] Therefore, capsaicin suppresses TPA-stimulated activation of NF-kB through inhibition of IkBa degradation and blockade of the subsequent nuclear translocation of p65 in human promyelocytic leukemia HL-60 cells. [24] Methylation of the phenolic hydroxyl group of capsaicin abolished its inhibitory effect on NF-kB DNA binding. Likewise, TPA-induced activation of AP-1 was mitigated by capsaicin treatment. [25] The aberrant activation of redox-sensitive transcription factors, such as, nuclear factor-kappa B (NF-kB), activator protein 1 (AP-1), cyclic adenosine monophosphate response element binding protein (CREB), and hypoxia inducible factor (HIF), has been found to contribute to carcinogenesis by promoting persistent inflammation, abnormal cell proliferation, evasion from apoptosis, angiogenesis, and so on. [24] Interestingly, a wide variety of dietary phytochemicals exert cancer chemopreventive properties by suppressing or blocking the inappropriate activation of aforementioned transcription factors. Also, transcription of genes involved in the activation of cellular antioxidant arsenal and carcinogen detoxification is largely regulated by another redox-sensitive transcription factor, that is, the NF-E2 related factor 2 (Nrf2), which plays a role in protecting cells / tissues from oxidative or electrophilic damage. Phytochemicals present in food potentially activate Nrf2, thereby, augmenting cellular antioxidant capacity and inducing expression of phase-2 detoxification enzymes. Hence, the modulation of cellular signaling, mediated by redox-sensitive transcription factors in the right direction represents a promising approach to achieving molecular target-based chemoprevention with edible phytochemicals. [24] Capsaicin was shown to inhibit human cancer androgen-resistant cell line, PC-3. [26] Capsaicin -induced apoptosis in prostate cells by a mechanism involving (ROS) generation, dissipation of the mitochondrial inner transmembrane potential DeltaPsi (m), and activation of caspase 3. This suggests that capsaicin is a promising anti-tumor agent in hormone refractory prostate cancer, which is resistant to many chemotherapeutic agents. [26] Capsaicin also induces apoptosis in PC-3 cells via ROS generation, c-Jun N-terminal kinase (JNK) activation, ceramide accumulation, and extracellular signal-regulated protein kinase (ERK) activation. [27] This mechanism undoubtedly explains the mechanism underlying the antiproliferative effect of capsaicin. In recent times, the effect of capsaicin, the main pungent ingredient of hot chilli peppers, in the gene expression profile of human prostate PC-3 cancer cells has been analyzed, using a microarray approach. [28] Accordingly, the upregulation of GADD153 / CHOP, an endoplasmic reticulum stress-regulated gene has been detected. This therefore suggests that capsaicin induces the antiproliferative effect through a mechanism facilitated by endoplasmic reticulum (ER) stress in prostate PC-3 cells. Capsaicin and Cell Cycle The cell cycle represents a series of tightly integrated events, involving the cyclins, cyclin-dependent kinases (CDKs), and some of the inhibitors of these molecules. [29],[30],[31] When activated, the CDKs provide a means for the cell to move from one phase of the cell cycle to the next (G1 to S or G2 to M). If cyclin and / or CDKs are affected, cell cycle arrest occurs. DNA damage within an intact cell results in the triggering of the apoptotic machinery. Some phytochemicals exert their anticancer activity by blocking cell cycle progression and triggering tumor cell apoptosis, which have become major indicators of an anticancer effect. [32],[33] The tumor suppressor protein p53 regulates the cellular response to DNA damage by mediating cell cycle arrest, DNA repair, and cell death. [34],[35] The mechanisms involved in p53-mediated cell death remain controversial, and regulation of the p53 function is complicated. Phosphorylation at the Ser-15 residue of p53 is critical for p53-dependent transactivation. In addition, accumulation of p53 protein by inhibiting the interaction between p53 and MDM2, stimulates p53-dependent transactivation. [36] In response to stress signals, the levels of p53 protein are rapidly increased, and activity is enhanced after phosphorylation at the Ser-15 residue, resulting in the upregulation of the downstream genes, including the cyclin-dependent kinase inhibitor p21WAF1/CIP1 and the proapoptotic gene Bax. In turn, increased levels of Bax induce mitochondrial depolarization, release of cytochrome c, and activation of caspase cascade, leading to apoptosis. [37],[38] Ataxia telangiectasia mutated kinase has been shown to phosphorylate the Ser-15 residue of p53, leading to apoptotic signal transduction. [39],[40] Several studies have demonstrated that the ROS generation phosphorylates and activates p53 in an ataxia telangiectasia mutated-dependent manner. [41],[42] Capsaicin also causes G1 arrest of endothelial cell through downregulation of cyclin D1 and vascular endothelia growth factor (VEGF)-induced angiogenic signaling pathways. [8] Sherr reported that cyclin D1 is required for the activity of cyclin-dependent 4(CDK4), which phosphorylates RB (retinoblastoma gene), thereby releasing E2F to mediate the transition of G1 to S , which in turn leads to DNA synthesis and cell cycle progression. [43] This pathway is blocked by capsaicin. It has been documented that other anti-angiogenic molecules such as, endostatin and curcumin also suppress retinoblastoma gene phosphorylation and DNA synthesis of endothelial cells through down regulation of cyclin D1. [42],[43],[44],[45] In fact, capsaicin was reported to block the downstream event of VEGF-induced KDR / FIK-1 signaling such as, the activation of p38 mitogen-activated protein kinase and p125 FAK tyrosine phosphorylation that are required for the mitogenic activity of VEGF in endothelial cells. [46],[47],[48] Cancer cells produce numerous blood vessels through which nutrients are siphoned from individuals carrying one form of cancer or the other. The activity of VEGF is needed to achieve this fit and is therefore dependent on its phosphorylation, before it becomes active. Capsaicin is known to block the phosphorylation of VEGF. Abnormal or improper activation of downstream transcription factor can result in uncontrolled cell growth, leading to malignant transformation, abnormal cell proliferation and growth. Capsaicin modulates the activities of proinflammatory mediators and intracellular signaling cascades Cytokines and chemokines have been shown to play an important role in a number of inflammatory diseases. [49] Palanki reported that in activated T cells, the transcription factors such as the activator protein-1 (AP-1), regulate the production of IL-2, matrix metalloproteinases, and the nuclear factor kappa b (NF-kB), which are essential for the transcription of proinflammatory cytokines such as 1L-1, IL-6, 1L-8, tumour necrosis factor (TNF), and the nuclear factor of activated T-cells (NFAT). [49] Interleukin-1L (IL-1α) also stimulates the production of prostaglandin E2 (PGE 2), increases the expression of COX-2 mRNA protein, phosphorylation of extracellular signal-regulated protein kinase-1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and C-Jun N-terminal kinase (JNK). [50] COX-1 is constitutively expressed while COX-2 is essentially inducible. Therefore, the expression of COX-2 is of pathological significance in a number of chronic inflammatory diseases. Scientific documentations have shown that IL-mediated transcription of COX-2 expression is regulated by numerous factors, such as, ERK, p38, NF-kB signaling pathway, and protein kinase C. [51],[52],[53],[54],[55] NF-kB is a dimeric protein that regulates the expression of genes involved in immune responses, inflammation, cell survival, and cancer. [54],[56] NF-kB is activated in response to various degrees of stimuli ranging from cytokines, chemokines, infectious agents, and radiation-induced DNA damage. NF- is bound to inhibitory protein Ikappa b in the cytoplasm. Phosphorylation of the 1kappa b leads to translocation of NF-kB into the nucleus where it drives the expression of target genes. [57],[58],[ 59] The inhibitory effects of capsaicin on NF-kB nuclear translocation has been extensively documented. [59],[60],[61] Topical application of capsaicin has been shown to inhibit phorbol myristate acetate (PMA) induced mouse-skin tumour formation in mouse skin blockage of cultured human leukemia HL-60 cells activation and attenuation of NF-kB and tumour promoter 12-0-tetradecanoyl phorbol-13-acetate (TPA-induced carcinogenesis. [59],[60],[62] Oxidative Action of Capsaicin Several studies have demonstrated that ROS generation plays a significant role in phosphorylation of p53 at the Ser-15 residue. [63],[64] Similarly, capsaicin-induced apoptosis in NB4 cells and in fresh leukemic cells from patients expressing wild-type p53 was associated with a significant increase in the levels of intracellular ROS, after glutathione (GSH) depletion. Similarly, pre-treatment with N-acetylcysteine (NAC), an excellent supplier of GSH inhibited phosphorylation of p53 at the Ser-15 residue, in the presence of capsaicin, indicating that ROS acts upstream of p53 phosphorylation by capsaicin. Moreover, reduction of H 2 O 2 by inhibited phosphorylation of p53 at the Ser-15 residue. It has been suggested that generation of ROS was a representative pathway of mitochondrial disruption in a p53-independent manner. [65] However, it is probable that over generation of ROS plays some role in capsaicin-induced mitochondrial depolarization and apoptosis in p53-defective cells. [66] Capsaicin and STAT3 Signaling Members of the signal transducer and activator of transcription (STAT) family of transcription factors have been reported to regulate the expression of gene products involved in cell survival, proliferation, chemoresistance, and angiogenesis. [67],[68] The activation of STATs involves the phosphorylation of a critical tyrosine residue by Janus-activated kinases (JAK) or the Src family kinases, leading to dimerization of STAT monomers, nuclear translocation, and binding to specific DNA response elements in the promoter region promoters of target genes. Among the STATs, STAT3 is perhaps the most intimately linked to tumourigenesis. [69] Although STAT3 is activated by interleukin-6 (IL-6), the epidermal growth factor and other growth factors. Constitutive activation of STAT3 has been discovered in a wide variety of tumours. [69],[70],[71],[72] STAT3 phosphorylation therefore plays a critical role in the transformation and proliferation of tumour cells. [70],[72] It has been found that capsaicin could suppress both constitutive and inducible STAT3 activation, and these effects are specific to STAT3, as capsaicin had no effect on STAT5 phosphorylation. Similarly, it has been observed that capsaicin suppressed nuclear translocation and the DNA-binding activity of STAT3 besides multiple myeloma cells and other forms of cancer, including head and neck cancers. Hepatocellular carcinoma, lymphomas, and leukemia also express constitutively active STAT3.The suppression of constitutively active STAT3 in multiple myeloma cells raises the possibility that this novel STAT3 inhibitor might also inhibit constitutively activated STAT3 in other types of cancer cells. STAT3 phosphorylation plays a critical role in the transformation and proliferation of tumor cells and capsaicin suppresses the expression of several STAT3-regulated proteins, including proliferative (cyclin D1), antiapoptotic (survivin, Bcl-2, and Bcl-xL), and angiogenic (VEGF) gene products. [70],[72] The downregulation of cyclin D1 expression by capsaicin correlates with suppression of proliferation and accumulation of cells in G 1 phase of the cell cycle. Conclusion The use of phytochemicals present in fruits and vegetable has gained worldwide acceptance as a novel source of chemopreventive agents against cancer cells. These non-nutrient phytochemicals either block or reverse multistage carcinogenesis. Capsaicin, a pungent ingredient present in chili pepper has anti-inflammatory, antioxidant, antiproliferative and anti-cancer potentials. Capsaicin has chemopreventive effect against a wide of chronic inflammatory diseases, including cancer. Other potential benefits of capsaicin should be explored with the aim of brightening our understanding of the molecular mechanism associated with its anti-cancer activities. References
Copyright 2010 - Indian Journal of Cancer The following images related to this document are available:Photo images[cn10012f8.jpg] [cn10012f5.jpg] [cn10012f3.jpg] [cn10012f1.jpg] [cn10012f6.jpg] [cn10012f2.jpg] [cn10012f7.jpg] [cn10012f4.jpg] |
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