Probenecid ameliorates testosterone‐induced benign prostatic hyperplasia: Implications of PGE‐2 on ADAM‐17/EGFR/ERK1/2 signaling cascade

Abstract

AbstractBenign prostatic hyperplasia (BPH) is one of the most prevalent clinical disorders in the elderly. Probenecid (Prob) is a well‐known FDA‐approved therapy for gout owing to its uricosuric effect. The present study evaluated the use of Prob for BPH as a COX‐2 inhibitor. Prob (100 and 200 mg/kg) was intraperitoneally injected into male Wistar rats daily for 3 weeks. In the second week, testosterone (3 mg/kg) was subcutaneously injected to induce BPH. Compared with BPH‐induced rats, Prob treatment reduced prostate weight and index and improved histopathological architecture. The protease activity of ADAM‐17/TACE and its ligands (TGF‐α and TNF‐α) were regulated by prob, which in turn abolished EGFR phosphorylation, and several inflammatory mediators (COX‐2, PGE2, NF‐κB (p65), and IL‐6) were suppressed. By reducing the nuclear import of extracellular regulated kinase protein 1/2 (ERK1/2), Prob helped re‐establish the usual equilibrium between antiapoptotic proteins like Bcl‐2 and cyclin D1 and proapoptotic proteins like Bax. All of these data point to Prob as a promising treatment for BPH because of its ability to inhibit COX‐2‐syntheiszed PGE2 and control the ADAM‐17/TGF‐α‐induced EGFR/ERK1/2 signaling cascade. These findings might help to repurpose Prob for the treatment of BPH.