Skip to main content

Advertisement

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

Article metrics

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. 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.

  2. 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.

  3. 3.

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

  4. 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.

  5. 5.

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

  6. 6.

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

  7. 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.

  8. 8.

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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 16.

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

  17. 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.

  18. 18.

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

  19. 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.

  20. 20.

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

  21. 21.

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

  22. 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.

  23. 23.

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

  24. 24.

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

  25. 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.

  26. 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.

Download references

Author information

Correspondence to Byung-Sam Kim.

Rights and permissions

Reprints and Permissions

About this article

Key words

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