Capsaicin and cancer

New review: Surh YJ. More Than Spice: Capsaicin in Hot Chili Peppers Makes Tumor Cells Commit Suicide. J Natl Cancer Inst 2002;94(17):1263-1265.

In this editorial to the Journal of the National Cancer Institute, Young-Joon Surh, from the College of Pharmacy, Seoul National University, South Korea, reviews the available pre-clinical cancer research of capsaicin (8-methyl-N-vanillyl-6-nonenamide). Capsaicin is a phenolic substance isolated from the plant genus capsicum (red hot chili peppers). The author notes that the role of capsaicin in carcinogenic processes is controversial. Although some investigators suspect that capsaicin is a carcinogen, co-carcinogen, or tumor promoter, others report that it possesses chemopreventive and chemotherapeutic effects.

Capsaicin can elicit neurogenic inflammation under certain physiologic conditions, but also possesses analgesic and anti-inflammatory activities, and is used in many topical creams and gels to mitigate neurogenic pain. A receptor for capsaicin and other structurally related substances has been identified and cloned. This receptor, vanilloid receptor subtype 1 (VR1), forms a nonselective cation channel in the plasma membrane that mediates some of the pleiotropic effects exerted by capsaicin and its analogues, which are collectively named vanilloids.

In vitro studies suggest that vanilloids can target both mitochondrial and plasma membrane electron transport systems, thereby generating reactive oxygen species that can mediate apoptosis (programmed cell death). Oxidative stress stimulated by vanilloid treatment of human cutaneous squamous cell carcinoma cells appears to be primarily of mitochondrial origin, and contributes to the death of these cells by apoptosis. The exact molecular milieu that characterizes elevated oxidative stress caused by vanilloid treatment is not clear and requires further investigation. In theory, such inappropriate reactive oxygen species generation may also have a deleterious effect on nonmalignant cells.

Background: Hot chili peppers of the plant genus capsicum are consumed worldwide as spices. Scientific evidence supports the use of topical capsaicin cream in the management of neuropathic pain related to diabetic neuropathy, postherpetic neuralgia, rheumatic diseases, and several other painful skin conditions. Intravesicular installation of capsaicin has been used for detrussor hyperreflexia. There is promising early evidence for the use of topical capsaicin for post-mastectomy pain and cluster headache. This editorial by Young-Joon Surh summarizes the available data regarding possible mechanisms of action of capsaicin, and potential anti-tumorogenic properties, particularly regarding cutaneous squamous cell carcinoma cells.

Capsaicin is likely safe when used topically as directed and when consumed moderately as a spice in foods (although effects of long-term topical use are not known). Excessive doses taken by mouth may cause gastrointestinal irritation. External use should be avoided on injured skin or near the eyes, due to caustic effects.

Capsaicin studies in the 1960s demonstrated analgesic effects in human and animal models of neurogenic inflammation. Research in the early 1980s found that cayenne may work by destroying the neuropeptide substance P, which mediates pain signals to the brain. When topically applied to the skin, capsaicin appears to stimulate and then block small diameter pain fibers by depleting substance P. Repeated application of capsaicin depletes nerve fibers of neuropeptides and prevents reaccumulation. Substance P may also activate inflammatory mediators in joint tissues (such as in arthritis). Capsaicin appears to effectively suppress histamine-induced pruritis in healthy skin, but has lesser effects in condition such as atopic eczema.

Studies of capsaicin in cancer are limited to in vitro and animal research of cytotoxicity, apoptosis, genotoxicity. Overall, published scientific data supports the use of topical capsaicin for relief of neuropathic pain.

References

1. Agrawal RC, Wiessler M, Hecker E, et al. Tumour-promoting effect of chilli extract in BALB/c mice. Int J Cancer 1986;38(5):689-695.
2. Baumann TK, Burchiel KJ, Ingram SL, et al. Responses of adult human dorsal root ganglion neurons in culture to capsaicin and low pH. Pain 1996;65(1):31-38.
3. Biro T, Brodie C, Modarres S, et al. Specific vanilloid responses in C6 rat glioma cells. Brain Res Mol Brain Res 1998;56(1-2):89-98.
4. Chitra S, Viswanathan P, Nalini N, et al. Role of redchilli (Capsaicin) in the formation of colonic carcinoma. Indian J Pathol Microbiol 1997;40(1):21-25.
5. Chueh PJ, Morre DJ, Wilkinson FE, et al. A 33.5-kDa heat- and protease-resistant NADH oxidase inhibited by capsaicin from sera of cancer patients. Arch Biochem Biophys 1997;342(1):38-47.
6. Hail N, Lotan R. Examining the role of mitochondrial respiration in vanilloid-induced apoptosis J Natl Cancer Inst 2002;94:1281-1292.
7. Hartung M, Leah J, Zimmerman M. The excitation of cutaneous nerve endings in a neuroma by capsaicin. Brain Res 1989;499(2):363-366.
8. Jang JJ, Kim SH, Yun TK. Inhibitory effect of capsaicin on mouse lung tumor development. In Vivo 1989;3(1):49-53.
9. Jung MY, Kang HJ, Moon A. Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation. Cancer Lett 2001;165:139-145.
10. Kim JD, Kim JM, Pyo JO, et al. Capsaicin can alter the expression of tumor forming-related genes which might be followed by induction of apoptosis of a Korean stomach cancer cell line, SNU-1. Cancer Lett 1997;120(2):235-241.
11. LaHann TR. Effect of capsaicin on croton oil and TPA induced tumorigenesis and inflammation. Proc West Pharmacol Soc 1986;29:145-149.
12. Lee YS, Kwon EJ, Jin Da Q, et al. Redox status-dependent regulation of cyclooxygenases mediates the capsaicin-induced apoptosis in human neuroblastoma cells. J Environ Pathol Toxicol Oncol 2002;21:113-120.
13. Lee YS, Nam DH, Kim JA. Induction of apoptosis by capsaicin in A172 human glioblastoma cells. Cancer Lett 2000;161(1):121-130.
14. Lopez-Carrillo L, Hernandez Avila M, Dubrow R. Chili pepper consumption and gastric cancer in Mexico: a case-control study. Am J Epidemiol 1994;139(3):263-271.
15. Macho A, Blázquez MV, Navas P, et al. Induction of apoptosis by vanilloid compounds does not require de novo gene transcription and activator protein 1 activity. Cell Growth Differ 1998;9:277-286.
16. Macho A, Calzado MA, Munoz-Blanco J, et al. Selective induction of apoptosis by capsaicin in transformed cells: the role of reactive oxygen species and calcium. Cell Death Differ 1999;6:155-165.
17. Macho A, Lucena C, Calzado MA, et al. Phorboid 20-homovanillates induce apoptosis through a VR1-independent mechanism. Chem Biol 2000;7:483-492.
18. Morre DJ, Caldwell S, Mayorga A, et al. NADH oxidase activity from sera altered by capsaicin is widely distributed among cancer patients. Arch Biochem Biophys 1997;342(2):224-230.
19. Morre DJ, Chueh PJ, Morre DM. Capsaicin inhibits preferentially the NADH oxidase and growth of transformed cells in culture. Proc Natl Acad Sci 1995;92(6):1831-1835.
20. Morre DJ, Sun E, Geilen C, et al. Capsaicin inhibits plasma membrane NADH oxidase and growth of human and mouse melanoma lines. Eur J Cancer. 1996;32A(11):1995-2003.
21. Park KK, Chun KS, Yook JI, Surh YJ. Lack of tumor promoting activity of capsaicin, a principal pungent ingredient of red pepper, in mouse skin carcinogenesis. Anticancer Res 1998;18(6A):4201-4205.
22. Park KK, Surh YJ. Effects of capsaicin on chemically-induced two-stage mouse skin carcinogenesis. Cancer Lett 1997;114(1-2):183-184.
23. Pascual DW, Bost KL, Xu-Amano J, et al. The cytokine-like action of substance P upon B cell differentiation. Reg Immunol 1992;4(2):100-104.
24. Patel PS, Varney ML, Dave BJ, et al. Regulation of constitutive and induced NF-kappaB activation in malignant melanoma cells by capsaicin modulates interleukin-8 production and cell proliferation. J Interferon Cytokine Res 2002;22(4):427-435.
25. Patel PS, Yang S, Li A, Varney ML, et al. Capsaicin regulates vascular endothelial cell growth factor expression by modulation of hypoxia inducing factor-1alpha in human malignant melanoma cells. J Cancer Res Clin Oncol. 2002;128(9):461-468.
26. Shimomura Y, Kawada T, Suzuki M. Capsaicin and its analogs inhibit the activity of NADH-coenzyme Q oxidoreductase of the mitochondrial respiratory chain. Arch Biochem Biophys 1989;270:573-577.
27. Singh S, Natarajan K, Aggarwal BB. Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is a potent inhibitor of nuclear transcription factor-kappa B activation by diverse agents. J Immunol 1996;157(10):4412-4420.
28. Surh Y. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 1999;428(1-2):305-327.
29. Surh YJ. More Than Spice: Capsaicin in Hot Chili Peppers Makes Tumor Cells Commit Suicide. J Natl Cancer Inst 2002;94(17):1263-1265.
30. Surh YJ, Lee E, Lee JM. Chemoprotective properties of some pungent ingredient present in red pepper and ginger. Mutat Res 1998;402:259-267.
31. Surh YJ, Lee RC, Park KK, et al. Chemoprotective effects of capsaicin and diallyl sulfide against mutagenesis or tumorigenesis by vinyl carbamate and N-nitrosodimethylamine. Carcinogenesis 1995;16(10):2467-2471.
32. Surh YJ, Lee SS. Capsaicin in hot chili pepper: carcinogen, co-carcinogen or anticarcinogen? Food Chem Toxicol 1996;34:313-316.
33. Surh YJ, Lee SS.Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential. Life Sci 1995;56(22):1845-1855.
34. Surh YJ. Anti-tumor promoting potential of selected spice ingredients with antioxidative and anti-inflammatory activities: a short review. Food Chem Toxicol. 2002;40(8):1091-1097.
35. Surh YJ. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res 1999;428:305-327.
36. Szallasi A, Blumberg PM. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol Rev 1999;51:159-211.
37. Tanaka T, Kohno H, Sakata K, et al. Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline 1-oxide-induced rat tongue carcinogenesis. Carcinogenesis 2002;23(8):1361-1367.
38. Teel RW, Huynh HT. Lack of the inhibitory effect of intragastrically administered capsaicin on NNK-induced lung tumor formation in the A.J mouse. In Vivo. 1999;13(3):231-234.
39. Toth B, Gannett P. Carcinogenicity of lifelong administration of capsaicin of hot pepper in mice. In Vivo 1992;6(1):59-63.
40. Watson CP, Evans RJ, Watt VR. The post-mastectomy pain syndrome and the effect of topical capsaicin. Pain 1989;38(2):177-186.
41. Wist E, Risberg T. Topical capsaicin in treatment of hyperalgesia, allodynia and dysesthetic pain caused by malignant tumour infiltration of the skin. Acta Oncol 1993;32(3):343.
42. Wolvetang EJ, Larm JA, Moutsoulas P, et al. Apoptosis induced by inhibitors of the plasma membrane NADH-oxidase involves Bcl-2 and calcineurin. Cell Growth Differ 1996;7:1315-1325.
43. Yoshitani SI, Tanaka T, Kohno H, Takashima S. Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone. Int J Oncol. 2001;19(5):929-939.