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-alpha-sensitive (RT4V6) and IFN-alpha-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-alpha, commonly used for treatment of bladder cancer. Whether the effects of curcumin are mediated through modulation of the nuclear factor-kappaB (NF-kappaB) pathway known to mediate antiapoptosis was investigated. Both gemcitabine and TNF activated NF-kappaB in bladder cancer cells and curcumin suppressed this activation. Similarly, cigarette smoke, a major risk factor for bladder cancer, also activated NF-kappaB and curcumin suppressed it. Cigarette smoke-induced expression of the NF-kappaB-regulated gene products cyclooxygenase-2 and vascular endothelial growth factor, linked with proliferation and angiogenesis, respectively, was also down-regulated by curcumin.