This exploratory grant seeks to establish a novel role for allium derivatives from garlic in control of human prosta cancer by acting as anti-androgens. Our preliminary observations reveal that when androgen-responsive human prostate cancer cells (LNCaP) are incubated with allium derivatives in vitro, two events take place: (a) the proliferation rate of the LNCaP cells is markedly reduced and (b) testosterone concentration rapidly decreases in both the media in which the cells are growing as well as in the cells themselves. Furthermore, when testosterone is added back to the media of LNCaP cells previously exposed to allium derivatives, the decrease in initial rate of cell proliferation is only partially restored. These preliminary results strongly suggest that allium-induced inhibition of cell proliferation and accelerated removal of testosterone are linked. We hypothesize that allium derivatives increase testosterone disappearance by accelerating conversion to inactive metabolites thereby diminishing the action of testosterone on the prostate. To test I validity of this hypothesis, we shall measure the conversion rate of testosterone to dihydrotestosterone (DHT), a more potent metabolite, through 5-alpha reductase, and the formation rate of a series of inactive testosterone metabolites, a determined by GC-MS methods. Concurrent with these experiments, we shall determine the mechanism of inhibition of growth of human prostat cancer cells by allium derivatives, whether by apoptosis or cytostasis. We shall determine where in the cell cycle growth inhibition occurs, whether or not apoptosis is induced, and whether changes in specific signal transduction proteins occ in later experiments, we shall examine effects of allium derivatives on regulatory proteins most likely to be relevant unc these conditions in modifying cell cycle transcription (i.e., cyclin B, cdk 2). These studies will then be extended in the second year to examine effects of allium derivatives on human prostate cancer cells (LNCaP C4-2) that exhibit androgen receptors but are non-responsive to its trophic effects. Together, the LNCaP and LNCaP C4-2 cell lines should serve as appropriate models, respectively, for early prostate cancer that is androgen-sensitive and later prostate cancer that is largely unresponsive to androgen manipulations. These studies should provide a creative approach to prevention and control of prostate cancer that is feasible and cosi effective, and should lead to an innovative advance in correlating certain dietary modifications and prostate cancer.
