Hydroxychloroquine modulates the progression of experimentally induced benign prostatic hyperplasia in rats via targeting EGFR/ERK/STAT3 and AR/FOXO1/TRAIL pathways: computational and in vivo studies
Abstract
Benign prostatic hyperplasia (BPH) is a prevalent progressive age-related disorder in men, yet its etiopathophysiology remains poorly understood. Current treatments like finasteride (Fin) have limited long-term efficacy, necessitating alternative therapies. Hydroxychloroquine (HCQ), a safe antimalarial agent, possesses anti-inflammatory, immunomodulatory, and antiproliferative activities, however, its therapeutic effect in BPH has not been investigated. Accordingly, we examined its therapeutic potential and underlying mechanisms, alone or combined with Fin, in testosterone-induced BPH in rats. In BPH-induced rats, HCQ markedly reduced prostate weight and index, and PSA, testosterone, dihydrotestosterone, pro-inflammatory cytokines (TNF-α, κ and IL-6), and the transcription factor "NF-κB" levels, while improving histological abnormalities in epithelial and stromal tissues. HCQ reduced the mRNA expression of AR and ERK1/2, and decreased the protein levels of EGFR and STAT3. Additionally, HCQ increased the mRNA expression of FOXO1 and promoted apoptosis through both intrinsic and TRAIL-mediated pathways. This was evidenced by the upregulation of pro-apoptotic Bax and the downregulation of anti-apoptotic Bcl-2 and Bcl-XL levels in the intrinsic pathway, as well as the reduction in mRNA expression of DR4 and DR5 in the TRAIL-mediated pathway. Notably, combining HCQ with Fin enhanced these effects. Molecular docking revealed HCQ's strong interactions with androgen receptor (AR),…
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