Milk Thistle Extract has been taken orally for centuries as an anti-hepatotoxic agent and is used as an over the counter medicine without any toxicity. We have shown that the active ingredient in this extract, silibinin, when fed to mice, inhibits the growth of prostate cancer xenografts without toxicity. Silibinin also blocks mitogenic signaling, cell cycle progression and growth of human tumor cells in culture, suggesting a direct effect of this compound on the neoplastic process. Our hypothesis is that silibinin targets multiple epigenetic molecular events such as impairment of mitogenic, cell survival and anti-apoptotic signaling and deregulated cell cycle progression involved in uncontrolled PCA growth and malignant progression. Together, these effects of silibinin, which are possibly inter-related, afford prevention, growth control and therapy of prostate cancer. Proposed specific aims are: I) To further identify and establish the efficacy of silibinin towards prevention, growth control and therapy of prostate cancer. II) To define and characterize the in vivo inhibitory effect of silibinin on mitogenic signaling in tumor tissues and further establish molecular mechanism in cell culture systems. III) To define and characterize the in vivo inhibitory effect of silibinin on cell cycle progression in tumor tissues and further establish molecular mechanism in cell culture systems. IV) To identify and define the mechanism of antiangiogenic potential of silibinin in PCA. We anticipate that proposed studies together with earlier work, will identify silibinin as a mechanism-based agent for the prevention, growth control and therapy of PCA, and will establish in vivo efficacy of silibinin in pre-clinical PCA model. As a practical and translational approach, the long-range goal of these studies will be to define and establish the usefulness of silibinin for the prevention and therapy of human prostate cancer. It is important to emphasize here that largely based on our completed studies and with FDA approval; we already have an ongoing phase IIII dose-escalation clinical trial (supported by NCI) with silibinin in prostate cancer patients with rising PSA. Completion of the studies proposed in this grant will provide us a """"""""head-start"""""""" to initiate clinical trials in prostate cancer patients to: 1) evaluate the efficacy of silibinin in PCA prevention, growth control and/or treatment; depending on the outcomes of proposed animal studies (in aim I), and 2) to establish the efficacy of silibinin employing surrogate endpoint biomarkers in prostate cancer clinical trials depending on the outcomes of proposed mechanistic studies (in aims lI-IV).
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