Sapanisertib is an orally bioavailable ATP-dependent high-potential raptor-mTOR (TORC1) inhibitor with antineoplastic activity. Here, the impact of sapanisertib was assessed on transforming growth factor-β1 (TGF-β1)-treated L929 and A549 cells and on a rat model of bleomycin pulmonary fibrosis. First, in A549 cells treated with TGF-β1, sapanisertib significantly suppressed the TGF-β1-induced epithelial-mesenchymal transition, with elevated and reduced E-cadherin and vimentin expression, respectively. In L929 cells treated with TGF-β1, sapanisertib significantly blocked the TGF-β1-induced cell proliferation, with decreases in the extracellular matrix-related proteins collagens I and III and smooth muscle actin and in the mechanism-related proteins hypoxia-inducing factor, mTOR, p70S6K, and Wnt5a. Compared with bleomycin alone, continuous gavage administration of sapanisertib for 14 days reduced pathological scores in bleomycin-induced pulmonary fibrosis rats, with decreases in collagen deposition and in the same proteins as in L929 and A549 cells. Accordingly, our findings show that sapanisertib can ameliorate experimental pulmonary fibrosis by inhibiting Wnt5a/mTOR/HIF-1α/p70S6K.
Keywords: HIF-1α; Wnt5a; mTOR; p70S6K; pulmonary fibrosis; sapanisertib.
© 2023 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.