Retinoids and Histone Deacetylase Inhibitors in the Treatment of Prostate Cancer.

摘要

Retinoids, derivatives of vitamin A (retinol), are required for the appropriate differentiation of normal human prostate epithelial cells. Human prostate cancer cells contain much lower levels of vitamin A and its metabolites than normal cells. We hypothesize that aberrant metabolism of vitamin A and dysregulation of gene expression in prostate tumor cells are related to the abnormal growth properties of the tumor cells. A rationale for using retinoids in prostate cancer chemotherapy is further supported by the effectiveness of ATRA (all-trans Retinoic Acid), a vitamin A metabolite, in the treatment of acute promyelocytic leukemia (APL) . We hypothesize that the efficacy of retinoic acid can be enhanced if it is administered in combination with low doses of selective, potent histone deacetylase inhibitors such as trichostatin A (TSA) or valproic acid. The goals of this idea grant are to use mouse xenograft models to ascertain the effectiveness of various retinoids plus histone deacetylase inhibitors in inhibiting the growth and inducing the differentiation of the human prostate cancer lines LNCaP and PC-3. A second goal of the project is to understand at the molecular level the mechanisms by which the combination of retinoic acid and histone deacetylase inhibitors result in human prostate tumor cell growth inhibition. In the past year we have performed a variety of biochemical and molecular biological assays on human prostate cancer cells treated with various combinations of the aforementioned drugs in order to gain more insight into the molecular mechanisms involved in cell growth inhibition. The studies that we have performed, and the studies proposed in the next period of this Idea Development grant should provide a much clearer rationale for new clinical treatments for prostate cancer in humans.