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

Benign 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.© 2023 Wiley Periodicals LLC.

Citation

Maha M Abdel-Fattah, Mohammed E Abo-El Fetoh, Hassan Afify, Laila A A Ramadan, Wafaa R Mohamed. Probenecid ameliorates testosterone-induced benign prostatic hyperplasia: Implications of PGE-2 on ADAM-17/EGFR/ERK1/2 signaling cascade. Journal of biochemical and molecular toxicology. 2023 Jun 23:e23450e23450

PMID: 37352135

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