The impact of finasteride and dutasteride treatments on proliferation, apoptosis, androgen receptor, 5α-reductase 1 and 5α-reductase 2 in TRAMP mouse prostates

Abstract

BackgroundPreviously, we studied the effect of finasteride- or dutasteride-containing diets in male C57BL/6 TRAMP x FVB mice. Pre (6 weeks of age) and post (12 weeks of age) groups received finasteride or dutasteride to determine the efficacy of these pharmaceuticals on prostate cancer (PCa) development in male C57BL/6 TRAMP x FVB mice. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment, and dutasteride treatments were more effective than finasteride treatments in decreasing prostatic intraepithelial neoplasia (PIN) progression and PCa development. Finasteride and Pre-Dutasteride treatments significantly decreased high-grade PIN incidence, but increased poorly differentiated PCa incidence. In this study, molecular changes in prostates of these mice were characterized in an effort to elucidate the discordant response in Pre-Dutasteride and finasteride groups, and determine why Post-Dutasteride treatment was more effective.Method/Principal findingsKi-67 (proliferation marker) and androgen receptor (AR) protein, apoptotic DNA fragmentation (TUNEL assay), 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) mRNA were quantified in male TRAMP mice prostate tissues with genitourinary weight < 1 and > 1 gram. Overall, proliferation and AR were decreased and apoptosis was increased in most tumors versus prostate epithelium and hyperplasia. Proliferation and AR were increased notably in hyperplasia versus prostate epithelium and tumor. There were no clear trends or differences in 5α-reductase 1 and 5α-reductase 2 levels between large and small tumors. The discordant response in Pre-Finasteride and Pre-Dutasteride groups may be due to upregulated 5αR1 levels in large versus small tumors. It is not clear what the mechanism is for the different response in the Post-Finasteride group. Post-Dutasteride treatment was more effective than Pre-Dutasteride treatment in decreasing 5αR1 in large tumors. Therefore, this may be why this treatment was more effective in decreasing PIN progression and PCa development.ConclusionThe effect of finasteride and dutasteride on these biomarkers did not clearly elucidate their mechanism of action, but tumor 5αR1 levels were significantly positively correlated with adjusted prostate severe lesion score.

Prostatic hyperplasia: Vascularization, hemodynamic and hormonal analysis of dogs treated with finasteride or orchiectomy

“…Thus, it was concluded that the sharp decrease in androgen profile (testosterone and DHT) after gonadectomy led to significant reduction in prostate blood flow. In fact, prostatic hemodynamics is primarily regulated by androgen hormones [55][56][57][58][59][60]. Thus, the expected reduction in prostate blood supply after testicle removal is an indirect signal of treatment effectiveness [52].…”

Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics

“…These lower number of CAG repeats have been previously associated with elevated AR expression. This finding is of therapeutic interest, given the availability of 5-alphahydrogenase inhibitors which have been shown to decrease AR expression 83 . The 5-alphahydrogenase inhibitors have been reported to lower the incidence of prostate cancer and are an FDA-approved treatment for benign prostatic hyperplasia (BPH) 84 .…”

Avaliação dos efeitos da finasterida sobre o desenvolvimento prostático intrauterino e pós-natal inicial de fêmeas e machos do gerbilo da Mongólia ("Meriones unguiculatus")

“…Sabe-se que a utilização da finasterida em tratamentos contra o câncer de próstata, de modo a reduzir a atividade androgênica e, por conseguinte, a proliferação tumoral Opoku-Acheampong et al, 2017), pode levantar preocupações acerca de sua forma livre no ambiente e dos efeitos que tal inibidor pode ter sobre o desenvolvimento prostático. Os poucos estudos relacionados à exposição intrauterina à finasterida em machos demonstraram que tal exposição, que causa redução nos níveis de DHT ao longo do desenvolvimento prostático inicial, pode gerar redução no tamanho da próstata, problemas na formação dos alvéolos, diminuição da atividade secretória e, em dosagens mais altas, não formação dos lobos prostáticos.…”