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

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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.
Publisher
SPANDIDOS PUBL LTD
Issue Date
2013-06
Language
English
Article Type
Article
Keywords

HEPATIC STELLATE CELLS; GROWTH-FACTOR-I; PHOSPHATIDYLINOSITOL 3-KINASE; PROSTATE-CANCER; TGF-BETA; DISEASE; KINASE; PROLIFERATION; EXPRESSION; APOPTOSIS

Citation

INTERNATIONAL JOURNAL OF ONCOLOGY, v.42, no.6, pp.2001 - 2008

ISSN
1019-6439
DOI
10.3892/ijo.2013.1905
URI
http://hdl.handle.net/10203/174029
Appears in Collection
CH-Journal Papers(저널논문)
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