SAT-329 Novel Dehydroepiandrosterone Derivatives Inhibiting Metastatic Prostate Cancer Cell Proliferation

Abstract: Metastatic prostate tumor cells mainly express type 1 5α-reductase and have been linked to antiandrogenic resistant prostate cancers. However, the isozyme of type 2 5α-reductase is mostly expressed in normal prostate epithelial cells and non-metastatic cancer cells of the prostate. Therefore, specific inhibitors of type 1 isozyme activity, could decrease the proliferation of these metastatic prostate tumors (in cell line LNCaP, for example). To demonstrate this, the antiproliferative activity of 16 new dehydroepiandrosterone derivatives, previously identified by our group as selective inhibitors of type 1 5α-reductase [1], were evaluated in LNCaP cultures in the presence of testosterone (T) or dihydrotestosterone (DHT) and/or finasteride (F). The viability of these cells was demonstrated by the formation of formazan crystals, which were quantified using a spectrophotometric technique. Western Blot analysis demonstrated the presence of type 1 5α-reductase protein in cells treated with T, T and F, or T plus each of the dehydroepiandrosterone derivatives evaluated. In addition, a significant decrease in LNCaP cell proliferation in cells treated with T plus these derivatives was detected, while T and T plus F treatments increased their spread. These data indicated that 5α-reductase activity in metastatic prostate cell line LNCaP was inhibited by all of the dehydroepiandrosterone derivatives analyzed and, as a consequence, cell proliferation decreased significantly. However, F, which is a specific blocker of type 2 5α-reductase, did not show any effect on cell proliferation compared to cells treated only with T. To determine the toxicity of these steroids, several groups of hamsters were treated with 2 mg/kg of each of these derivatives once every 24 hours for six days. The body weight of these animals increased over six days similarly to that of control hamsters. The weights of prostate and seminal vesicles of the control and treated animals showed no significant differences. In conclusion, 16 new dehydroepiandrosterone derivatives showed an antiproliferative effect on LNCaP cells, due to the inhibition of type 1 5α-reductase activity. In addition, these derivatives showed no toxicity in the tested model. Therefore, these derivatives have significant potential for therapeutical use. Reference: [1] Bratoeff et al. GENZ 2013, 28 (6): 1247-1254. Nothing to Disclose: MC, LB, YH.