Bladder cancer is the most common type of cancer linked to occupational and environmental exposure to harmful chemical substances. Such substances are absorbed into bloodstream, filtered by kidneys, and stored in the bladder. Exposure of bladder tissue and lining to harmful substances eventually causes cancer. Standard treatment for bladder cancer includes surgery, chemo and radiation therapy, biological therapy, and combinations of these. However, surgery has undesirable physical and psychological effects, metastases are difficult to treat, and recurrence occurs. One approach to control bladder cancer growth and metastasis could be its prevention by phytochemicals; this approach has had a renewed public and scientific interest for the prevention of different epithelial cancers. Overall, human cancers appear to involve a gradual accumulation of genetic and epigenetic changes over a period of years. For example, alone or in combination, cell signaling, cell cycle and apoptosis regulators, and angiogenesis are identified as critical, perhaps causal, epigenetic events associated with tumor growth, progression and metastasis of several malignancies including bladder cancer. Together, these studies suggest that agents that could modulate these targets/events will be potent cancer preventive agents in general and bladder cancer in particular. Our recent studies in different human cancer cells show that silibinin inhibits cell signaling, modulates cell cycle regulators causing G1/G2-M arrest and leads to differentiation and/or apoptosis, and prevents skin and prostate cancers in mouse models. Together, hypothesis proposed is: silibinin is a novel bladder cancer preventive agent, and anti-cancer effect of silibinin involves inhibition of cell survival signaling leading to anti-proliferative and apoptotic efficacy. Following aims would establish bladder cancer preventive efficacy of silibinin. 1) To assess and define the effect of silibinin on cell survival signaling in normal bladder epithelial and bladder carcinoma HTB2 cells. 2) To assess and establish the efficacy of silibinin in human bladder carcinoma HTB2 xenograft growth and regression in nude mice. As a practical and translational approach, we believe that outcome of proposed studies will form a firm basis for a well-developed R01 grant to further define and establish the efficacy of silibinin against bladder cancer and the molecular mechanisms associated with its effects.
