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Research Articles: Therapeutics, Targets, and Development

Curcumin potentiates the apoptotic effects of chemotherapeutic agents and cytokines through down-regulation of nuclear factor-B and nuclear factor-B–regulated gene products in IFN-–sensitive and IFN-–resistant human bladder cancer cells

Departments of ¹ Urology and Cancer Biology and ² Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Bharat B. Aggarwal, Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 143, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-3503; Fax: 713-794-1613; E-mail: aggarwal{at}mdanderson.org

Abstract

Bladder cancer mortality varies between the countries; whereas being highest in Western countries, it is lowest in Eastern countries, such as India. Cigarette smoking is one of the major risk factors for bladder cancer in affluent nations, such as United States. Localized early-stage bladder cancer is treated with resection and intravesical cytokine therapy, whereas metastatic cancer is typically treated with various combinations of systemic chemotherapy. Whether curcumin, a yellow curry pigment commonly consumed in countries, such as India, has any role in prevention or treatment of bladder cancer was investigated. We found that curcumin inhibited the proliferation, induced cell cycle arrest, and DNA fragmentation in both IFN-–sensitive (RT4V6) and IFN-–resistant (KU-7) bladder cancer cells. Curcumin also potentiated the apoptotic effects of the chemotherapeutic agents (gemcitabine and paclitaxel) and of cytokines [tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand]. This effect of curcumin was independent of sensitivity and resistance to IFN-, commonly used for treatment of bladder cancer. Whether the effects of curcumin are mediated through modulation of the nuclear factor-B (NF-B) pathway known to mediate antiapoptosis was investigated. Both gemcitabine and TNF activated NF-B in bladder cancer cells and curcumin suppressed this activation. Similarly, cigarette smoke, a major risk factor for bladder cancer, also activated NF-B and curcumin suppressed it. Cigarette smoke–induced expression of the NF-B–regulated gene products cyclooxygenase-2 and vascular endothelial growth factor, linked with proliferation and angiogenesis, respectively, was also down-regulated by curcumin. [Mol Cancer Ther 2007;6(3):1022–30]

Grant support: Clayton Foundation for Research (B.B. Aggarwal and A.M. Kamat), NIH P01 grant CA91844 on lung chemoprevention (B.B. Aggarwal), NIH Bladder Specialized Programs in Research Excellence 5 P50 CA091846-03 (Project PI; A.M. Kamat), and grant 5P30 CA016672-32 for flow cytometric analysis.

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.

Note: A.M. Kamat and G. Sethi contributed equally to this work.

Received 8/31/06; revised 1/ 4/07; accepted 1/31/07.

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