title: Comparative studies of 5 alpha-reductase inhibitors within MCF-7 human breast cancer cells.
abstract: We have compared the inhibitory effects of six synthetic steroid analogs (17 beta-carboxy-4-androsten-3-one benzylanilide (VP-1), 17 alpha-acetoxy-6-methylene-4-pregnene-3,20-dione (VP-2), 6-methylene-4-pregnene-3,20-dione (VP-3), 17 beta-acetoxy-6-methylene-4-androsten-3-one (VP-4), 17 beta-acetoxy-16,16-dimethyl-6-methylene-4-androsten-3-one (VP-5), and 3 beta-hydroxy-16-methylene-5-androsten-17-one (VP-6) ) upon 5 alpha-reductase activity within MCF-7 human breast cancer cells and rat prostate. Enzyme assays were performed by quantifying the amounts of [3H]5 alpha-androstan-3 alpha-17 beta-diol and/or [3H]dihydrotestosterone formed from 40 nM [3H]testosterone within each system. Five microM concentrations of VP-2 and VP-3 inhibited prostatic 5 alpha-reductase by 55 and 65%, respectively, whereas the other analogs showed little activity. In contrast, each of the six analogs was active against MCF-7 homogenate 5 alpha reductase activity. VP-2 and VP-4 demonstrated approx 65 and 70% inhibitions, respectively, whereas the other four compounds inhibited enzyme activity by 40-55% in this system. These results suggest that rat prostate and MCF-7 cells contain different 5 alpha-reductase isozymes. When these agents were examined for 5 alpha-reductase inhibitory activity following 1 h preincubations with intact MCF-7 cultures, VP-1 and 3 demonstrated potencies similar to those in MCF-7 homogenate. The other compounds, however, were far less active under these conditions. Longer culture preincubations (16 h) were associated with substantially increased VP-6 potency, moderate increases for VP-4 and 5, but no change in VP-2 activity. Additional studies examining the abilities of these agents to bind to MCF-7 androgen receptor (AR) and progesterone receptor (PR) revealed moderate AR binding activities of VP-2, 3, and 4, and substantial PR binding for VP-2 and 3. Finally, VP-4 failed to inhibit estrogen-dependent MCF-7 PR synthesis, suggesting that it has no androgenic activity despite its ability to interact with MCF-7 AR.
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005260:Female; D006801:Humans; D008297:Male; D008777:Methyltestosterone / Q000031:analogs & derivatives / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011374:Progesterone / Q000031:analogs & derivatives / Q000494:pharmacology; D011467:Prostate / Q000201:enzymology; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; C036790:6-methylene-4-pregnene-3,20-dione; C032364:17-acetoxy-6-methylene-4-pregnene-3,20-dione; D011374:Progesterone; D010088:Oxidoreductases; D008777:Methyltestosterone