This pilot proposal is to evaluate the efficacy of the combination regimens of bioactive phytochemicals for prevention of prostate cancer progression by targeting simultaneously multiple steps involved in tumorigenesis. Prostate tumorigenesis involves in multiple critical steps, such as uncontrolled cancer cell growth and enhanced tumor angiogenesis. Dietary or nutritional modification has been considered to be an effective regimen for prevention and treatment of certain types of cancer including prostate cancer. Previous research has made considerable progress in identifying active dietary components. On the other hand, it has been recognized that cancer incidence and progression may not be reduced to the full extent possibly by single agents, and even promising agents usually show significant toxicity at efficacious doses. Therefore the combination of multiple agents based on differences in the mechanisms of cancer inhibition is expected to increase efficacy and/or reduce toxicity. Considerable data have indicated that combinations of agents that target cancer cell growth and tumor angiogenesis respectively may provide more effective regimens in an additive or a synergistic manner for prevention of prostate cancer progression. We have applied cellular function-based assays to identify the potent components for inhibition of cancer cell growth or suppression of angiogenesis, and have identified, from a group of active dietary components, sulforaphane and silybin as the most potent components for inhibition of prostate cancer cell growth and for suppression of angiogenesis respectively. Thus this pilot proposal is designed to test our hypothesis that the combination of sulforaphane and silybin may synergistically prevent the progression of prostate cancer.
Specific Aim 1 is to determine the effect of sulforaphane and silybin combination on the growth of androgen-dependent and androgen- independent human prostate tumors in animal models. Orthotopic prostate tumor models for androgen- sensitive (LNCaP) and androgen-independent (PC-3) prostate cancers will be used to evaluate the preventive effects of sulforaphane and silybin combinations on prostate cancer progression.
Specific Aim 2 is to identify biomarkers that are associated with and may be responsible for the possible synergistic effects of sulforaphane and silybin combinations in vivo. We will first determine a series of cellular markers that are associated with tumor cell proliferation, apoptosis and tumor angiogenesis (Aim 2a). In addition, cDNA microarray assays will be performed to identify potential molecular targets that may provide new insights into the molecular mechanisms of synergistic combinations (Aim 2b). We expect the proposed studies will allow us to verify possible synergistic effects between sulforaphane and silybin combinations on prevention of prostate cancer progression. Determinations of cellular biomarkers and identification of candidate molecular markers should provide sufficient preliminary data for further mechanism elucidation in the future RO1 proposal application.
