Department of Urology, University of Wisconsin, Madison, Wisconsin, USA.
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Prostate. 2024 Oct;84(14):1309-1319. doi: 10.1002/pros.24766. Epub 2024 Jul 14.
Benign prostatic hyperplasia (BPH) is a condition generally associated with advanced age in men that can be accompanied by bothersome lower urinary tract symptoms (LUTS) including intermittency, weak stream, straining, urgency, frequency, and incomplete bladder voiding. Pharmacotherapies for LUTS/BPH include alpha-blockers, which relax prostatic and urethral smooth muscle and 5ɑ-reductase inhibitors such as finasteride, which can block conversion of testosterone to dihydrotestosterone thereby reducing prostate volume. Celecoxib is a cyclooxygenase-2 inhibitor that reduces inflammation and has shown some promise in reducing prostatic inflammation and alleviating LUTS for some men with histological BPH. However, finasteride and celecoxib can reduce mitochondrial function in some contexts, potentially impacting their efficacy for alleviating BPH-associated LUTS.
To determine the impact of these pharmacotherapies on mitochondrial function in prostate tissues, we performed immunostaining of mitochondrial Complex I (CI) protein NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) and inflammatory cells on BPH specimens from patients naïve to treatment, or who were treated with celecoxib and/or finasteride for 28 days, as well as prostate tissues from male mice treated with celecoxib or vehicle control for 28 days. Quantification and statistical correlation analyses of immunostaining were performed.
NDUFS3 immunostaining was decreased in BPH compared to normal adjacent prostate. Patients treated with celecoxib and/or finasteride had significantly decreased NDUFS3 in both BPH and normal tissues, and no change in inflammatory cell infiltration compared to untreated patients. Mice treated with celecoxib also displayed a significant decrease in NDUFS3 immunostaining and no change in inflammatory cell infiltration.
These findings suggest that celecoxib and/or finasteride are associated with an overall decrease in NDUFS3 levels in prostate tissues but do not impact the presence of inflammatory cells, suggesting a decline in mitochondrial CI function in the absence of enhanced inflammation. Given that BPH has recently been associated with increased prostatic mitochondrial dysfunction, celecoxib and/or finasteride may exacerbate existing mitochondrial dysfunction in some BPH patients thereby potentially limiting their overall efficacy in providing metabolic stability and symptom relief.
良性前列腺增生（BPH）通常与男性的老年有关，可伴有烦人的下尿路症状（LUTS），包括间歇性、弱流、用力、尿急、尿频和不完全排空膀胱。LUTS/BPH 的药物治疗包括松弛前列腺和尿道平滑肌的α受体阻滞剂，以及 5α-还原酶抑制剂，如非那雄胺，它可以阻止睾酮转化为二氢睾酮，从而减少前列腺体积。塞来昔布是一种环氧化酶-2 抑制剂，可减轻炎症，并已显示出在减轻一些患有组织学 BPH 的男性的前列腺炎症和 LUTS 方面有一定的前景。然而，在某些情况下，非那雄胺和塞来昔布会降低线粒体功能，从而可能影响它们缓解 BPH 相关 LUTS 的疗效。
为了确定这些药物治疗对前列腺组织中线粒体功能的影响，我们对未经治疗的患者或接受塞来昔布和/或非那雄胺治疗 28 天的患者的 BPH 标本以及接受塞来昔布或载体对照治疗 28 天的雄性小鼠的前列腺组织进行了线粒体复合物 I（CI）蛋白 NADH 脱氢酶[泛醌]铁硫蛋白 3（NDUFS3）和炎性细胞的免疫染色。对免疫染色进行了定量和统计学相关性分析。
与正常相邻前列腺相比，NDUFS3 在 BPH 中染色减少。与未接受治疗的患者相比，接受塞来昔布和/或非那雄胺治疗的患者在 BPH 和正常组织中的 NDUFS3 均显著降低，而炎性细胞浸润无变化。接受塞来昔布治疗的小鼠也显示 NDUFS3 免疫染色显著减少，炎性细胞浸润无变化。
这些发现表明，塞来昔布和/或非那雄胺与前列腺组织中 NDUFS3 水平的整体下降有关，但不影响炎性细胞的存在，表明在没有增强炎症的情况下，线粒体 CI 功能下降。鉴于 BPH 最近与前列腺线粒体功能障碍增加有关，塞来昔布和/或非那雄胺可能会使一些 BPH 患者现有的线粒体功能障碍恶化，从而可能限制它们在提供代谢稳定性和缓解症状方面的整体疗效。
