Abstract
Here we demonstrated that SKI2162, a small-molecule inhibitor of the TGF-β type I receptor (ALK5), prevented radiation-induced fibrosis (RIF) in mice. SKI2162 inhibited phosphorylation of Smad and induction of RIF-related genes in vitro. In RIF a mouse model, SKI2162 reduced late skin reactions and leg-contracture without jeopardizing the acute skin reaction. Irradiation of mouse tissue increased COL1A2 mRNA levels, and topical administration of SKI2162 significantly inhibited this effect. Thus, these findings support that SKI2162 has potential value as novel RIF-protective agent, and could be candidate for clinical trials.
Highlights
Radiation therapy (RT) is among the main cancer treatment modalities together with surgery and chemotherapy, and about half of all newly diagnosed patients will receive RT during the course of their disease [1]
The present study showed that the activation of the TGF-β signaling pathway by radiation, which has been regarded as a major mechanism in the pathogenesis of Radiation-induced fibrosis (RIF), was effectively controlled by SK2162, leading to the amelioration of RIF in a mouse www.impactjournals.com/oncotarget model
Among the various signaling molecules involved in fibrosis, TGF-β1 has been described as the master switch for the fibrotic mechanism [3,4,5]
Summary
Radiation therapy (RT) is among the main cancer treatment modalities together with surgery and chemotherapy, and about half of all newly diagnosed patients will receive RT during the course of their disease [1]. Radiation can activate the TGF-β signaling pathway, and continuous expression of TGF-β has been observed in the early and late phases of RIF [6, 7]. This signaling pathway involves TGF-β binding to the TGF-β type II receptor, which recruits the TGF-β type I receptor, known as ALK5 (activin receptor-like kinase-5), resulting in the assembly of a heterodimeric receptor complex [8]. There have been numerous attempts to develop anti-fibrotic agents targeting the TGF-β signaling pathway, including TGF-β-neutralizing antibodies, antisense oligonucleotides against TGF-β, and TGF-β receptor antagonists [10]
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