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J. Biol. Chem., Vol. 280, Issue 8, 6301-6308, February 25, 2005

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Sensitization of Taxol-induced Apoptosis by Curcumin Involves Down-regulation of Nuclear Factor-B and the Serine/Threonine Kinase Akt and Is Independent of Tubulin Polymerization^*

Smitha V. Bava, Vineshkumar T. Puliappadamba, Ayswaria Deepti, Asha Nair, Devarajan Karunagaran, and Ruby John Anto

From the Division of Cancer Biology, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala-695014, India

Taxol is the best anticancer agent that has ever been isolated from plants, but its major disadvantage is its dose-limiting toxicity. In this study, we report with mechanism-based evidence that curcumin, a nontoxic food additive commonly used by the Indian population, sensitizes tumor cells more efficiently to the therapeutic effect of Taxol. A combination of 5 nM Taxol with 5 µM curcumin augments anticancer effects more efficiently than Taxol alone as evidenced by increased cytotoxicity and reduced DNA synthesis in HeLa cells. Furthermore, our results reveal that this combination at the cellular level augments activation of caspases and cytochrome c release. This synergistic effect was not observed in normal cervical cells, 293 cells (in which Taxol down-regulates nuclear factor-B (NF-B)), or HeLa cells transfected with inhibitor B double mutant (IB DM), although the transfection itself sensitized the cells to Taxol-induced cytotoxicity. Evaluation of signaling pathways common to Taxol and curcumin reveals that this synergism was in part related to down-regulation of NF-B and serine/threonine kinase Akt pathways by curcumin. An electrophoretic mobility shift assay revealed that activation of NF-B induced by Taxol is down-regulated by curcumin. We also noted that curcumin-down-regulated Taxol induced phosphorylation of the serine/threonine kinase Akt, a survival signal which in many instances is regulated by NF-B. Interestingly, tubulin polymerization and cyclin-dependent kinase Cdc2 activation induced by Taxol was not affected by curcumin. Altogether, our observations indicate that Taxol in combination with curcumin may provide a superior therapeutic index and advantage in the clinic for the treatment of refractory tumors.

Received for publication, September 15, 2004 , and in revised form, October 20, 2004.

^* This work was supported in part by grants from the Department of Biotechnology, the Government of India, and the Science, Technology, and Environment Department, Government of Kerala, India. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 91-471-2347975; Fax: 91-471-2348096; E-mail: rubyjohnanto{at}yahoo.com.

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