Epidemiologic and laboratory studies demonstrate that genistein, a major soy isoflavone, and 3,3′-diindolylmethane (DIM), a phytochemical abundant in cruciferous vegetables, provide a protective effect against prostate cancer, but the molecular basis for their function in the prostate has not been fully investigated. We report here the effects of DIM and genistein on estradiol (E2) induced proliferation in LNCaP cells and the effects of DIM and genistein on estrogen metabolism in both LNCaP and PC-3 cells. Utilizing MTS proliferation assays, we have confirmed previous reports that E2 increases the proliferation of LNCaP cells in a time and dose dependent manner and have shown that both DIM and genistein diminish this proliferative effect. Additionally, we have found that the combination of DIM and genistein causes a greater reduction in E2 induced proliferation than either DIM or genistein alone, suggesting that DIM and genistein can work synergistically to provide a protective effect against prostate cancer. Moreover, we have found, by real time RT-PCR, that both DIM and genistein increase the expression of the estrogen metabolizing enzymes cytochrome P450 1A1 (CYP1A1) and catechol-O-methyltransferase (COMT) in both LNCaP and PC-3 cells, and decrease the expression of 17-β-hydroxysteriod dehydrogenase type 2 (17-β-HSD type 2) in PC-3 cells. In conjuction, utilizing mass spectroscopy, we have found that DIM and genistein decrease the conversion of estrone to 16-hydroxyestrone, and potentially increase the conversion of 2-hydroxyestrone to 2-methoxyestrone in PC-3 cells. Taken together these results suggest that one of the mechanisms by which DIM and genistein exert cancer-preventive effects in the prostate may involve modulation of estrogen metabolism away from the production of potentially carcinogenic estrogen metabolites. Further investigations are underway to determine if DIM and genistein alter estrogen metabolism in vivo and to determine if DIM and/or genistein act as estrogen agonists in prostate cancer cells.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]