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Capsaicin induces apoptosis by generating reactive oxygen species and disrupting mitochondrial transmembrane potential in human colon cancer cell lines

Abstract

Although genetic factors are a well-known cause of colorectal cancer, environmental factors contribute more to its development. Despite advances in the fields of surgery, radiotherapy and chemotherapy, the cure rates for colon cancer have not substantially improved over the past few decades. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the principal pungent ingredient of hot chili pepper, has exhibited an anti-tumor effect in many cell types. However, the mechanisms responsible for the anti-tumor effect of capsaicin are not yet completely understood. In this study, we investigated whether capsaicin induces apoptosis in colon cancer cell lines. Capsaicin decreased cell viability in a dose-dependent manner in Colo320DM and LoVo cells. In addition, capsaicin produced cell morphology changes and DNA fragmentation, decreased the DNA contents, and induced phosphatidylserine translocation, which is a hallmark of apoptotic cell death. We showed that capsaicin-induced apoptosis is associated with an increase in ROS generation and a disruption of the mitochondrial transmenbrane potential. A possible mechanism of capsaicin-induced apoptosis is the activation of caspase 3, a major apoptosis-executing enzyme. Treatment with capsaicin induced a dramatic increase in caspase 3 activity, as assessed by the cleavage of Ac-DEVD-AMC, a fluorogenic substrate. In conclusion, our results clearly showed that capsaicin induced apoptosis in colon cancer cells. Although the actual mechanisms of capsaicin-induced apoptosis remain uncertain, it may be a beneficial agent for colon cancer treatment and chemoprevention.

Abbreviations

ΔΨm :

mitochondrial transmembrane potential

MTT:

13-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide

PI:

propidium iodide

ROS:

reactive oxygen species

References

  1. Hall, P.A., Coates, P.J., Ansari, B. and Hopwood, D. Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. J. Cell Sci. 107 (1994) 3569–3577.

    PubMed  CAS  Google Scholar 

  2. Bedi, A., Pasricha, P.J., Alchtar, A.J., Barber, J.P., Bedi, G.C., Giairdiello, F.M., Zahnbauer, B.A., Hamitlton, S.R. and Jones, R.J. Inhibition of apoptosis during development of colorectal cancer. Cancer Res. 55 (1995) 1811–1816.

    PubMed  CAS  Google Scholar 

  3. Cordell, G.A. and Araujo, O.E. Capsaicin: identification, nomenclature, and pharmacotherapy. Ann. Pharm. 27 (1993) 330–336.

    CAS  Google Scholar 

  4. Govindarajan, V.S. and Sathyanarayana, M.N. Capsaicin-production, technology, chemistry, and quality. Part V. Impact on physiology, pharmacology, nutrition, and metabolism: structure, pungent, pain, and desensitization sequences. CRC Crit. Rev. Food Sci. Nutr. 29 (1991) 435–474.

    CAS  Article  Google Scholar 

  5. Dray, A. Neuropharmacological mechanisms of capsaicin and related substances. Biochem. Pharmacol. 44 (1992) 611–615.

    PubMed  Article  CAS  Google Scholar 

  6. Holzer, P. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol. Rev. 43 (1991) 144–201.

    Google Scholar 

  7. Szallasi, A. and Blumberg, P. Specific binding of resiniferatoxin, an ultrapotent capsaicin analog, by dorsal root ganglion membranes. Brain Res. 524 (1990) 106–111.

    PubMed  Article  CAS  Google Scholar 

  8. Szallasi, A. and Blumberg, P. Vanilloid (capsaicin) receptor and mechanisms. Pharmacol Rev. 51 (1999) 159–211.

    PubMed  CAS  Google Scholar 

  9. Castillo-Olivares, A., Yantiri, F., Chueh, P.J., Wang, S., Sweeting, M., Sedlak, D., Morre, D.M., Burgess, J. and Morre, D.J. A drug-responsive and protease-resistant peripheral NADH oxidase complex from the surface of HeLa S cells. Arch. Biochem. Biophys. 358 (1998) 125–140.

    PubMed  Article  Google Scholar 

  10. Ito, K., Nakazato, T., Murakami, A., Yamato, K., Miyakawa, Y., Yamada, T., Hozumi, N., Ohigashi, H., Ikeda, Y. and Kizaki, M. Induction of apoptosis in leukemic cells by homovanillic acid derivative, capsaicin, through oxidative stress: implication of phosphorylation of p53 at Ser-15 residue by reactive oxygen species. Cancer Res. 64 (2004) 1071–1078.

    PubMed  Article  CAS  Google Scholar 

  11. Kim, J.D., Kim, J.M., Pyo, J.O., Kim, S.Y., Kim, B.S., Yu, R., and Han, I.S. Capsaicin can alter the expression of tumor forming-related genes followed by induction of apoptosis of a Korean stomach cancer line, SNU-1. Cancer Lett. 120 (1997) 235–241.

    PubMed  Article  CAS  Google Scholar 

  12. Kim, C.S., Park, W.H., Park, J.Y., Kang, J.H., Kim, M.O., Kawada, T., Yoo, H., Han I.S. and Yu R. Capsaicin, a spicy component of hot pepper, induces apoptosis by activation of the proliferator-activated receptor gamma in HT-29 human colon cancer cells, J. Med. Food 7 (2004) 267–273.

    PubMed  CAS  Google Scholar 

  13. Lee, Y.S., Kang, Y.S., Lee, J.S., Nicolova, S. and Kim, J.A. Involvement of NADPH oxidase-mediated generation of reactive oxygen species in the apoptotic cell death by capsaicin in HepG2 human hepatoma cells. Free Radic Res. 38 (2004) 405–412.

    PubMed  Article  CAS  Google Scholar 

  14. Kim, S. and Moon, A. Capsaicin-induced apoptosis of H-ras-transformed human breast epithelial cells is Rac-dependent via ROS generation, Arch. Pharmacol. Res. 27 (2004) 845–849.

    Article  CAS  Google Scholar 

  15. Mori, A., Lehmann, S., O’Kelly, J., Kumagai, T., Desmond, J.C., Pervan, M., McBride, W.H., Kizaki, M. and Koeffler, H.P. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells, Cancer Res. 66 (2006) 3222–3229.

    PubMed  Article  CAS  Google Scholar 

  16. Vaux, D.L. and Korsmeyer, S.J. Cell death in development. Cell 96 (1999) 245–254.

    PubMed  Article  CAS  Google Scholar 

  17. Mori, A., Lehmann, S., O’Kelly, J., Kumagai, T., Desmond, J.C., Pervan, M., McBride, W.H., Kizaki, M. and Koeffler, H.P. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res. 66 (2006) 3222–3229.

    PubMed  Article  CAS  Google Scholar 

  18. Vermeulen, K., Van Bockstaele, D.R. and Berneman, Z.N. Apoptosis: mechanisms and relevance in cancer. Ann. Hematol. 84 (2005) 627–639.

    PubMed  Article  CAS  Google Scholar 

  19. Sánchez, A.M., Sánchez, M.G., Malagarie-Cazenave, S., Olea, N. and Díaz-Laviada, I. Induction of apoptosis in prostate tumor PC-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis 11 (2006) 89–99.

    PubMed  Article  CAS  Google Scholar 

  20. Desagher, S. and Martinou, J.C. Mitochondria as the central control point of apoptosis. Trends Cell Biol. 10 (2000) 369–377.

    PubMed  Article  CAS  Google Scholar 

  21. Loeffler, M. and Kroemer, G. The mitochondrion in cell death control: certainties and incognita. Exp. Cell Res. 256 (2000) 19–26.

    PubMed  Article  CAS  Google Scholar 

  22. Macho, A, Calcado, M.A., Munoz-Blanco, J., Gomez-Diaz, C., Gajate, C., Mollinedo, F., Navas, P. and Munoz, E. Selective induction of apoptosis by capsaicin in transformed cells: The role of reactive oxygen species and calcium. Cell Death Differ. 6 (1999) 155–165.

    PubMed  Article  CAS  Google Scholar 

  23. Cohen, G.M. Caspases: the executioners of apoptosis. Biochem. J. 326 (1997) 1–16.

    PubMed  CAS  Google Scholar 

  24. Green, D.R. and Reed, J.C. Mitochondria and apoptosis. Science 281 (1998) 1309–1312.

    PubMed  Article  CAS  Google Scholar 

  25. Jänicke, R.U., Sprengart, M.L., Wati, M.R. and Porter, A.G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem. 273 (1998) 9357–9360.

    PubMed  Article  Google Scholar 

  26. Woo, M, Hakem, R, Soengas, M.S., Duncan, G.S., Shahinian, A., Kägi, D., Hakem, A., McCurrach, M., Khoo, W., Kaufman, S.A., Senaldi, G., Howard, T. and Mak, T.W. Essential contribution of caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12 (1998) 806–819.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Byung-Sam Kim.

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Yang, K.M., Pyo, J.O., Kim, GY. et al. Capsaicin induces apoptosis by generating reactive oxygen species and disrupting mitochondrial transmembrane potential in human colon cancer cell lines. Cell Mol Biol Lett 14, 497–510 (2009). https://doi.org/10.2478/s11658-009-0016-2

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  • DOI: https://doi.org/10.2478/s11658-009-0016-2

Key words

  • Capsaicin
  • Colon cancer cell line
  • Apoptosis
  • Mitochondrial transmembrane potential
  • Reactive oxygen species
  • Caspase 3