BIOFLAVONOIDS, TYPE-II [H-3] ESTRADIOL BINDING-SITES AND PROSTATIC-CANCER CELL-PROLIFERATION

Previous studies from this laboratory have shown that bioflavonoids in cluding luteolin and quercetin possess antiestrogenic activity in the female reproductive tract and appear to elicit this activity by intera ction with type II [H-3]estradiol binding sites in the cell nucleus. S tudies by a number of laboratories including our own have shown that t ype II sites are present in the rodent prostate gland and therefore, w e suspected that administration of bioflavonoids such as luteolin may antagonize prostate growth through type LT site binding interactions a s well. The studies presented in this report demonstrate that the mous e prostatic tissue does contain nuclear type II sites and that oral ad ministration of luteolin for 14 days results in a significant (p<0.01) reduction in prostatic weight in intact male mice without significant effects on the seminal vesicular, testis or body weights of these ani mals. These results suggest that luteolin is a prostate specific antag onist under these experimental conditions. In vitro studies with LNCaP and PC-3 human prostate cancer cell lines demonstrated that luteolin treatment resulted in a dose dependent inhibition of prostate cancer c ell proliferation which was maximum 4-8 days following treatment. Whol e cell binding studies demonstrated that both LNCaP and PC-3 cells con tained very high concentrations of type II [H-3]estradiol binding site s (>200,000 sites/cell) relative to levels previously reported for oth er tissues and cells and luteolin was capable of interacting with thes e sites in prostate cancer cells. In fact, there was a direct correlat ion between the type II site occupancy by luteolin and the inhibition of LNCaP or PC-3 prostatic cancer cell proliferation by this bioflavon oid. Flow cytometric analysis revealed that luteolin treatment caused an accumulation of LNCaP cells in G(2)/M (p<0.01) and reduced the frac tions of LNCaP cells in S-phase undergoing apoptosis (p<0.01). Similar ly, luteolin treatment also arrested PC-3 cells in G(2)/M (p<0.01) and reduced the proportion of cells in G(0)/G(1) (p<0.05). This being the case, it is not surprising that this bioflavonoid also blocked the gr owth of subcutaneous PC-3 cell xenografts in athymic nude mice. These data demonstrate that naturally occurring type TI site antagonists suc h as luteolin are capable of inhibiting normal and malignant prostatic cell growth and proliferation in vitro and in viva and may possess pr ophylactic as well as therapeutic activities against prostatic prolife rative diseases including benign prostatic hyperplasia (BPH) and prost ate cancer.