Abstract
Background5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) convert testosterone into the more potent androgen dihydrotestosterone. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have increased 5αR1 and decreased 5αR2 expression. Previously, finasteride (5αR2 inhibitor) treatment begun 3 weeks post-tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5αR1 expression or activity. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, whereas dutasteride (5αR1 and 5αR2 inhibitor) treatment would decrease tumor growth regardless of whether treatment was initiated before or after tumor implantation.Methodology/Principal FindingsSixty 8-week-old male nude mice were randomized to Control, Pre- and Post-Finasteride, and Pre- and Post-Dutasteride (83.3 mg drug/kg diet) diet groups. Pre- and post-groups began their treatment diets 1–2 weeks prior to or 3 weeks after subcutaneous injection of 1×105 WPE1-NA22 human prostate cancer cells, respectively. Tumors were allowed to grow for 22 weeks; tumor areas, body weights, and food intakes were measured weekly. At study's conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control; dutasteride intake significantly decreased seminal vesicle weights compared to finasteride intake. No differences were measured in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells and parent line RWPE-1 prostate epithelial cells were unaltered by treatment with testosterone, dihydrotestosterone, or mibolerone, suggesting that these cell lines are not androgen-sensitive.ConclusionThe lack of response of WPE1-NA22 prostate cancer cells to androgen treatment may explain the inadequate tumor growth observed. Additional studies are needed to determine whether finasteride and dutasteride are effective in decreasing prostate cancer development/growth.
Highlights
Prostate cancer is the most commonly diagnosed malignancy in men, estimated to account for nearly 30% of cancer cases in 2011 [1]
Testosterone, the main circulating androgen, is converted by the isoenzymes 5a-reductase 1 and 5a-reductase 2 into the more potent dihydrotestosterone, which binds with up to ten-fold higher affinity to the androgen receptor than testosterone [2,3]. 5areductase 1 is the major isoenzyme in human liver and nongenital skin, whereas 5a-reductase 2 is the major isoenzyme in the prostate, epididymis, seminal vesicle, and genital skin [4]
We examined the effect of finasteride and dutasteride diets begun 1 week before or 3 weeks after subcutaneous injection of WPE1-NA22 human prostate cancer cells into the rear flanks of male nude mice
Summary
Prostate cancer is the most commonly diagnosed malignancy in men, estimated to account for nearly 30% of cancer cases in 2011 [1]. 5areductase 1 is the major isoenzyme in human liver and nongenital skin, whereas 5a-reductase 2 is the major isoenzyme in the prostate, epididymis, seminal vesicle, and genital skin [4]. Most studies report increased 5a-reductase 1 and decreased 5areductase 2 mRNA expression or activity in prostate cancer [6,7,8,9]. Two 5a-reductase inhibitors, finasteride (5a-reductase 2 inhibitor) and dutasteride (5a-reductase 1 and 2 inhibitor), are commonly used to treat benign prostatic hyperplasia (BPH) [12]. These 5areductase inhibitors could be used to prevent or treat prostate cancer by reducing dihydrotestosterone levels [13]
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