Archives of Pharmacal Research

, 27:1147 | Cite as

Capsaicin-induced apoptosis and reduced release of reactive oxygen species in MBT-2 Murine Bladder Tumor cells

  • Ji-Seon Lee
  • Jong-Sun Chang
  • Ji Youl Lee
  • Jung-Ae Kim
Research Article Article

Abstract

Bladder cancer is a common cancer with high risk of recurrence and mortality. Intravesicle chemotherapy after trans-urethral resection is required to prevent tumor recurrence and progression. It has been known that antioxidants enhance the antitumor effect of bacillus Calmette-Guerin (BCG), the most effective intravesical bladder cancer treatment. Capsaicin, the major pungent ingredient in genusCapsicum, has recently been tried as an intravesical drug for overactive bladder and it has also been shown to induce apoptotic cell death in many cancer cells. In this study, we investigated the apoptosis-inducing effect and alterations in the cellular redox state of capsaicin in MBT-2 murine bladder tumor cells. Capsaicin induced apoptotic MBT-2 cell death in a time- and dose-dependent manner. The capsaicin-induced apoptosis was blocked by the pretreatment with Z-VAD-fmk, a broad-range caspase inhibitor, or AcDEVD-CHO, a caspase-3 inhibitor. In addition to the caspase-3 activation, capsaicin also induced cytochrome c release and decrease in Bcl-2 protein expression with no changes in the level of Bax. Furthermore, capsaicin at the concentration of inducing apoptosis also markedly reduced the level of reactive oxygen species and lipid peroxidation, implying that capsaicin may enhance the antitumor effect of BCG in bladder cancer treatment. These results further suggest that capsaicin may be a valuable intravesical chemotherapeutic agent for bladder cancers.

Key words

Capsaicin Bladder cancer Apoptosis Reactive oxygen species Bcl-2 Cytochromec release Caspase-3 

References

  1. Akaza, H., Hinotsu, S., Aso, Y., Kakizoe, T., and Koiso, K., Bacillus Calmette-Guerin treatment of existing papillary bladder cancer and carcinoma in situ of the bladder. Four-year results.Cancer, 75, 552–559 (1995).PubMedCrossRefGoogle Scholar
  2. Bombeli, T., Karsan, A., Tait, J. F., and Harlan, J. M., Apoptotic vascular endothelial cells become procoagulant.Blood, 89, 2429–2442 (1997).PubMedGoogle Scholar
  3. Borner, C., The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions.Mol. Immunol., 39, 615–647 (2003).PubMedCrossRefGoogle Scholar
  4. Cerutti, P. A., Prooxidant states and tumor promotion.Science, 227, 375–381 (1985).PubMedCrossRefGoogle Scholar
  5. Cordell, G. A. and Araujo, O. E., Capsaicin: identification, nomenclature, and pharmacotherapy.Ann. Pharmacother., 27, 330–336 (1993).PubMedGoogle Scholar
  6. Denis, G., Humblet, C., Verlaet, M., Boniver, J., and Defresne, M. P., p53, Bax and Bcl-2in vivo expression in the murine thymus after apoptogenic treatments.Anticancer Res., 18, 3315–3321 (2000).Google Scholar
  7. De Ridder, D., Chandiramani, V., Dasgupta, P., Van Poppel, H., Baert, L., and Fowler, C. J., Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: a dual center study with long-term followup.J. Urol., 158, 2087–2092 (1997).PubMedCrossRefGoogle Scholar
  8. Galati, G. and O’Brien, P. J., Cytoprotective and anticancer properties of coenzyme Q versus capsaicin.Biofactors, 18, 195–205 (2003).PubMedGoogle Scholar
  9. Green, D. R. and Reed, J. C., Mitochondria and apoptosis.Science, 281, 1309–1312 (1998).PubMedCrossRefGoogle Scholar
  10. Gross, A., McDonnell, J. M., and Korsmeyer, S. J., BCL-2 family members and the mitochondria in apoptosis.Genes Dev, 13, 1899–1911 (1999).PubMedCrossRefGoogle Scholar
  11. Haunstetter, A. and Izumo, S., Apoptosis; basic mechanism and implications for cardiovascular disease.Circ. Res., 82, 1111–1129 (1998).PubMedGoogle Scholar
  12. Herrmann, M., Lorenz, H. M., Vollm, R., Grunkem, M., Woithm, W., and Kaldenm, J. R., A rapid and simple method for the isolation of apoptotic DNA fragments.Nucleic Acids Res., 22, 5506–5507 (1994).PubMedCrossRefGoogle Scholar
  13. Ito, K., Nakazato, T., Yamato, K., Miyakawa, Y., Yamada, T., Hozumi, N., Segawa, K., 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, 1071–1078 (2004).PubMedCrossRefGoogle Scholar
  14. Jemal, A., Murray, T., Samuels, A., Ghafoor, A., Ward, E., and Thun, M. J.,Cancer statistics, 2003.CA Cancer J. Clin., 53, 5–26 (2003).PubMedCrossRefGoogle Scholar
  15. Jung, M. Y., Kang, H. J., and Moon, A., Capsaicin-induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation.Cancer Lett., 165, 139–145 (2001).PubMedCrossRefGoogle Scholar
  16. Kang, H. J., Soh, Y., Kim, M. S., Lee, E. J., Surh, Y. J., Kim, H. R., Kim, S. H., and Moon, A., Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in rastransformed human breast epithelial cells.Int. J. Cancer, 103, 475–482 (2003).PubMedCrossRefGoogle Scholar
  17. Lamm, D. L., Superficial bladder cancer.Curr. Treat. Options Oncol., 3, 403–411 (2002).PubMedCrossRefGoogle Scholar
  18. Lee, Y. S., Nam, D. H., and Kim, J. A., Induction of apoptosis by capsaicin in A172 human glioblastoma cells.Cancer Lett., 161, 121–130 (2000).PubMedCrossRefGoogle Scholar
  19. Lee, Y. S., Kwon, E. J., Jin, D. Q., Park, S. H., Kang, Y. S., Huh, K., and Kim, J. A. Redox status-dependent regulation of cyclooxygenases mediates the capsaicin-induced apoptosis in human neuroblastoma cells.J. Environ. Pathol. Toxicol. Oncol., 21, 113–120 (2002).PubMedGoogle Scholar
  20. Lee, Y. S., Kang, Y. S., Lee, J. S., Nikolova, S., and Kim, J. A., Involvement of NADPH oxidase-mediated generation of reactive oxygen species in the apototic cell death by capsaicin in HepG2 human hepatoma cells.Free Rad. Res., 38, 405–412 (2004).CrossRefGoogle Scholar
  21. Liu, X., Kim, C. N., Yang, J., Jemmerson, R., and Wang, X., Induction of apoptotic program in cell-free extracts; Requirement for dATP and cytochromec.Cell, 86, 147–157 (1996).PubMedCrossRefGoogle Scholar
  22. Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.J. Immunol. Methods, 65, 55–63 (1983).PubMedCrossRefGoogle Scholar
  23. Pook, S. H., Esuvaranathan, K., and Mahendran, R.,N-Acetylcysteine augments the cellular redox changes and cytotoxic activity of internalized mycobacterium bovis in human bladder cancer cells.J. Urol., 168, 780–785 (2002).PubMedCrossRefGoogle Scholar
  24. Sternberg, C. N., A critical review of the management of bladder cancer.Crit. Rev. Oncol. Hematol., 31, 193–207 (1999).PubMedCrossRefGoogle Scholar
  25. Surh, Y. J. and Lee, S. S., Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential.Life Sci., 56, 1845–1855 (1995).PubMedCrossRefGoogle Scholar
  26. Surh, Y. J., Lee E., and Lee, J. M., Chemoprotective properties of some pungent ingredients present in red pepper and ginger.Mutat. Res., 402, 259–267 (1998).PubMedGoogle Scholar
  27. Surh, Y. J., More than spice: capsaicin in hot chili peppers makes tumor cells commit suicide.J. Natl. Cancer Inst. 94, 1263–1265 (2002).PubMedGoogle Scholar
  28. Suzuki, T. and Iwai, K., Constitution of red pepper species: chemistry, biochemistry, pharmacology, and food science of the pungent principle of Capsicum species, in: A. Brosi (Ed.), The Alkaloides, 23, Academic Press, New York, 1994, pp. 227–299.Google Scholar
  29. Szatrowski, T. P. and Nathan, C. F., Production of large amounts of hydrogen peroxide by human tumor cells.Cancer Res., 51, 794–798 (1991).PubMedGoogle Scholar
  30. Tanaka, T., Kohno, H., Sakata, K., Yamada, Y., Hirose, Y., Sugie, S., and Mori, H., Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline l-oxide-induced rat tongue carcinogenesis.Carcinogenesis, 23, 1361–1367 (2002).PubMedCrossRefGoogle Scholar
  31. Tanaka, T., Kohno, H., Sakata, K., Yamada, Y., Hirose, Y., Sugie, S., and Mori, H., Modifying effects of dietary capsaicin and rotenone on 4-nitroquinoline l-oxideinduced rat tongue carcinogenesis.Carcinogenesis, 23, 1361–1367 (2002).PubMedCrossRefGoogle Scholar
  32. Tu, Y., Xu, F. H., Liu, J., Vescio, R., Berenson, J., Fady, C., and Lichtenstein, A., Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide.Blood, 88, 1805–1812 (1996).PubMedGoogle Scholar
  33. Zhang, J., Nagasaki, M., Tanaka, Y., and Morikawa, S., Capsaicin inhibits growth of adult T-cell leukemia cells.Leuk. Res., 27, 275–283 (2003).PubMedCrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2004

Authors and Affiliations

  • Ji-Seon Lee
    • 2
  • Jong-Sun Chang
    • 2
  • Ji Youl Lee
    • 1
    • 2
  • Jung-Ae Kim
    • 2
  1. 1.Department of Urology, College of MedicineCatholic University of KoreaSeoulKorea
  2. 2.College of PharmacyYeungnam UniversityGyongsanKorea

Personalised recommendations