Resveratrol and piperine enhance radiosensitivity of tumor cells

  • Tak, Jean-Kyoung (School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University) ;
  • Lee, Jun-Ho (School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University) ;
  • Park, Jeen-Woo (School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University)
  • Received : 2011.10.31
  • Accepted : 2011.12.26
  • Published : 2012.04.30


The use of ionizing radiation (IR) is essential for treating many human cancers. However, radioresistance markedly impairs the efficacy of tumor radiotherapy. IR enhances the production of reactive oxygen species (ROS) in a variety of cells which are determinant components in the induction of apoptosis. Much interest has developed to augment the effect of radiation in tumors by combining it with radiosensitizers to improve the therapeutic ratio. In the current study, the radiosensitizing effects of resveratrol and piperine on cancer cells were evaluated. Cancer cell lines treated with these natural products exhibited significantly augmented IR-induced apoptosis and loss of mitochondrial membrane potential, presumably through enhanced ROS generation. Applying natural products as sensitizers for IR-induced apoptotic cell death offers a promising therapeutic approach to treat cancer.


Apoptosis;Ionizing radiation;Natural products;Radiosensitizer;Redox status


Supported by : National Research Foundation of Korea


  1. Kabakov, A. E., Kudryavtsev, V. A. and Gabai, V. L. (2010) Hsp90 inhibitors as promising agents for radiotherapy. J. Mol. Med. 88, 241-247.
  2. Camphausen, K. and Tofilon, P. J. (2004) Combining radiation and molecular targeting in cancer therapy. Cancer Biol. Ther. 3, 247-250.
  3. Moeller, B. J., Dreher, M. R., Rabbani, Z. N., Schroeder, T., Cao, Y., Li, C. Y. and Dewhirst, M. W. (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cells 8, 99-110.
  4. Smets, L. A. (1994) Programmed cell death (apoptosis) and response to anti-cancer drugs. Anticancer Drugs 5, 3-9.
  5. von Sonntag, C. (2006) Free Radical-induced DNA Damage and Its Repair. A Chemical Perspective. Springer, Berlin.
  6. Pinthus, J. H., Bryskin, I., Trachtenberg, J., Lu, J. P., Singh, G., Fridman, E. and Wilson, B. C. (2007) Androgen induces adaptation to oxidative stress in prostate cancer: implications for treatment with radiation therapy. Neoplasia 9, 68-80.
  7. Wang, J. and Yi, J. (2008) Cancer cell killing via ROS: to increase or decrease, that is the question. Cancer Biol. Ther. 7, 1875-1884.
  8. Ben-Yoseph, O. and Ross, B. D. (1994) Oxidation therapy: the use of a reactive oxygen species-generating enzyme system for tumor treatment. Br. J. Cancer 70, 1131-1135.
  9. Yoshikawa, T., Kokura, S., Tainaka, K., Naito, Y. and Kondo, M. (1995) A novel cancer therapy based on oxygen radicals. Cancer Res. 55, 1617-1620.
  10. Baur, J. A. and Sinclair, D. A. (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Discov. 5, 493-506.
  11. Orallo, F. (2006) Comparative studies of the antioxidant effects of cis- and trans-resveratrol. Curr. Med. Chem. 13, 87-98.
  12. Murias, M., Jager, W., Handler, N., Erker, T., Horvath, Z., Szekeres, T., Nohl, H. and Gille, L. (2005) Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure-activity relationship., Biochem. Pharmacol. 69, 903-912.
  13. Heiss, E. H., Schilder, Y. D. and Dirsch, V. M. (2007) Chronic treatment with resveratrol induces redox stressand ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells. J. Biol. Chem. 282, 26759-26766.
  14. Sunila, E. S. and Kuttan, G. (2004) Immunomodulatory and antitumor activity of Piper longum Linn. and piperine. J. Ethnopharmacol. 90, 339-346.
  15. Mikkelsen, R. B. and Wardman, P. (2003) Biological chemistry of reactive oxygen and nitrogen and radiation-induced signal transduction mechanisms. Oncogene 22, 5734-5754.
  16. Ahmed, K. M. and Li, J. J. (2008) NF-kappa B-mediated adaptive resistance to ionizing radiation. Free Radic. Biol. Med. 44, 1-13.
  17. Creagh, E. M. and Martin, S. J. (2001) Caspases: cellular demolition experts. Biochem. Soc. Trans. 29, 696-702.
  18. Li, H., Zhu, H., Xu, C. J. and Yuan, J. (1998) Cleavage of Bid by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491-501.
  19. Pastorino, J. G., Simbula, G., Yamamoto, K., Glascott, P. A., Rothman, R. J. and Farber, J. L. (1996) The cytotoxicity of tumor necrosis factor depends on induction of the mitochondrial permeability transition. J. Biol. Chem. 271, 29792-29798.
  20. Tauskela, J. S., Hewitt, K., Kang, L. P., Comas, T., Gendron, T., Hakim, A., Hogan, M., Durkin, J. and Morley, P. (2001) Evaluation of glutathione-sensitive fluorescent dyes in conical culture. Glia 30, 329-341.
  21. Tak, J. K. and Park, J.-W. (2009) The use of ebselen for radioprotection in cultured cells and mice. Free Radic. Biol. Med. 46, 1177-1185.
  22. Sundaresan, M., Yu, Z. X., Ferrans, C. J., Irani, K. and Finkel, T. (1995) Requirement for generation of $H_{2}O_{2}$ for platelet-derived growth factor signal transduction. Science 270, 296-299.

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