A novel PI3K inhibitor alleviates fibrotic responses in fibroblasts derived from Peyronie's plaques

Abstract

Peyronie's disease (PD) is fibrosis localized in the tunica albuginea that is characterized by penile deformity and curvature. The pathogenesis of this disease remains unclear even though transforming growth factor-beta (TGF-beta)/smad signalling has been reported to be associated with PD. Recent studies have shown that phosphoinositide 3-kinase (PI3K)/Akt signalling regulates fibrotic responses including collagen synthesis and cell proliferation. Thus, we synthesized HS-173, a novel PI3K inhibitor, and determined whether this compound has anti-fibrotic effects on PD-derived primary fibroblasts. In this study, we found that HS-173 inhibited the growth of fibroblasts in a dose-dependent manner and induced apoptosis. In addition, HS-173 reduced the expression of alpha-smooth muscle actin (alpha-SMA), vimentin, PAI-1, fibronectin, collagen type I, collagen IV and TGF-beta-activated smad2/3 in PD-derived primary fibroblasts. HS-173 blocked the PI3K/Akt signalling pathway by decreasing the activation of Akt, mTOR and P70S6K. Our results showed that HS-173 suppressed fibrotic responses such as cell proliferation and collagen synthesis by blocking PI3K/Akt signalling in PD-derived primary fibroblasts. Our findings provide molecular insights into the potential therapeutic action of HS-173 through targeting the PI3K/Akt pathway in PD-derived fibroblasts and demonstrated that HS-173 could be used as a pharmacological agent for treating other fibrotic diseases.