Abstract
Current attempts to improve the survival of cancer patients largely depend on strategies to target tumor cell resistance. Naturally occurring dietary compounds such as resveratrol have gained considerable attention as cancer chemopreventive agents. Here, we report that resveratrol acts as potent sensitizer for anticancer drug-induced apoptosis by inducing cell cycle arrest, which in turn resulted in survivin depletion. Concomitant analysis of cell cycle and apoptosis revealed that pretreatment with resveratrol resulted in cell cycle arrest in S phase and apoptosis induction preferentially out of S phase upon subsequent drug treatment. Likewise, cell cycle arrest in S phase by cell cycle inhibitors enhanced drug-induced apoptosis. Resveratrol-mediated cell cycle arrest sensitized for apoptosis by downregulating survivin expression through transcriptional and post-transcriptional mechanisms. Similarly, downregulation of survivin expression using survivin antisense oligonucleotides sensitized for drug-induced apoptosis. Importantly, downregulation of survivin and enhanced drug-induced apoptosis by resveratrol occurred in various human tumor cell lines irrespective of p53 status. Thus, this combined sensitizer (resveratrol)/inducer (cytotoxic drugs) concept may be a novel strategy to enhance the efficacy of anticancer therapy in a variety of human cancers.
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References
Altieri DC . (2003). Nat. Rev. Cancer, 3, 46–54.
Ashkenazi A and Dixit VM . (1998). Science, 281, 1305–1308.
Bernhard D, Tinhofer I, Tonko M, Hubl H, Ausserlechner MJ, Greil R, Kofler R and Csordas A . (2000). Cell Death Differ., 7, 834–842.
Bierau J, Van Gennip AH, Leen R, Helleman J, Caron HN and Van Kuilenburg AB . (2003). Int. J. Cancer, 103, 387–392.
Cal C, Garban H, Jazirehi A, Yeh C, Mizutani Y and Bonavida B . (2003). Curr. Med. Chem. Anti-Cancer Agents, 3, 77–93.
Cory S and Adams JM . (2002). Nat. Rev. Cancer, 2, 647–656.
Debatin KM, Poncet D and Kroemer G . (2002). Oncogene, 21, 8786–8803.
Deveraux QL and Reed JC . (1999). Genes Dev., 13, 239–252.
Fulda S, Susin SA, Kroemer G and Debatin KM . (1998). Cancer Res., 58, 4453–4460.
Fulda S, Meyer E and Debatin KM . (2000). Cancer Res., 60, 3947–3956.
Fulda S, Kuefer M, Dockhorn-Dworniczak B and Debatin KM . (2001). Oncogene, 20, 5865–5877.
Fulda S, Meyer E and Debatin KM . (2002). Oncogene, 21, 2283–2294.
Goyal L . (2001). Cell, 104, 805–808.
Gusman J, Malonne H and Atassi G . (2001). Carcinogenesis, 22, 1111–1117.
Hengartner MO . (2000). Nature, 407, 770–777.
Herr I and Debatin KM . (2001). Blood, 98, 2603–2614.
Igney FH and Krammer PH . (2002). Nat. Rev. Cancer, 2, 277–288.
Kaufmann SH and Earnshaw WC . (2000). Exp. Cell Res., 256, 42–49.
Kim B and Feldman EL . (2002). J. Biol. Chem., 277, 27393–27400.
Kong AN, Yu R, Hebbar V, Chen C, Owuor E, Hu R, Ee R and Mandlekar S . (2001). Mutat. Res., 480–481, 231–241.
Kroemer G and Reed JC . (2000). Nat. Med., 6, 513–519.
Johnstone RW, Ruefli AA and Lowe SW . (2002). Cell, 108, 153–164.
Lowe SW and Lin AW . (2000). Carcinogenesis, 21, 485–495.
Mahotka C, Wenzel M, Springer E, Gabbert HE and Gerharz CD . (1999). Cancer Res., 59, 6097–6102.
Olie RA, Simoes-Wust AP, Baumann B, Leech SH, Fabbro D, Stahel RA and Zangemeister-Wittke U . (2000). Cancer Res., 60, 2805–2809.
Park EJ and Pezzuto JM . (2002). Cancer Metast. Rev., 21, 231–255.
Pucci B, Kasten M and Giordano A . (2000). Neoplasia, 2, 291–299.
Salvesen GS and Duckett CS . (2002). Nat. Rev. Mol. Cell. Biol., 3, 401–410.
Scaffidi C, Fulda S, Debatin KM, Krammer PK and Peter ME . (1998). EMBO J., 17, 1675–1687.
Sherr CJ . (2000). Cancer Res., 60, 3689–3695.
Smith DM, Gao G, Zhang X, Wang G and Dou QP . (2000). Int. J. Mol. Med., 6, 503–507.
Thornberry N and Lazebnik Y . (1998). Science, 281, 1312–1316.
van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ and Vandenabeele P . (2002). Cell Death Differ., 9, 1031–1042.
Vousden KH and Lu X . (2002). Nat. Rev. Cancer, 2, 594–604.
Walczak H and Krammer PH . (2000). Exp. Cell Res., 256, 58–66.
Wallace-Brodeur RR and Lowe SW . (1999). Cell Mol. Life Sci., 55, 64–75.
Zhao J, Tenev T, Martins LM, Downward J and Lemoine NR . (2000). J. Cell Sci., 113, 4363–4371.
Acknowledgements
We thank PH Krammer (Heidelberg, Germany) for anti-FLIP antibody, B Vogelstein (Baltimore, MA, USA) for p53-deficient HCT116 cells and Petra Miller-Rostek and Melanie Preißinger for expert technical assistance. This work has been partially supported by grants from the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe, the Bundesministerium für Forschung und Technologie, Wilhelm-Sander-Stiftung, Else-Kröner-Stiftung, the Deutsche Kinderkrebsstiftung and the European Community (to KMD and SF).
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Fulda, S., Debatin, KM. Sensitization for anticancer drug-induced apoptosis by the chemopreventive agent resveratrol. Oncogene 23, 6702–6711 (2004). https://doi.org/10.1038/sj.onc.1207630
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DOI: https://doi.org/10.1038/sj.onc.1207630
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