Autophagy protects against dasatinib-induced hepatotoxicity via p38 signaling

// Xiaochun Yang 1 , Jincheng Wang 1 , Jiabin Dai 1 , Jinjin Shao 1 , Jian Ma 2 , Chao Chen 2 , Shenglin Ma 3 , Qiaojun He 1 , Peihua Luo 1 and Bo Yang 1 1 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China 2 Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, China 3 Nanjing Medical University, Affiliated Hangzhou Hospital, Hangzhou First People’s Hospital, Hangzhou, China Correspondence: Peihua Luo, email: // Bo Yang, email: // Keywords : Autophagy, p38 signaling, Hepatotoxicity, Dasatinib Received : October 14, 2014 Accepted : January 14, 2015 Published : January 31, 2015 Abstract Liver dysfunction is a common side effect associated with the treatment of dasatinib and its mechanism is poorly understood. Autophagy has been thought to be a potent survival or death factor for liver dysfunction, which may shed the light on a novel strategy for the intervention of hepatotoxicity caused by dasatinib. In this study, we show for the first time that autophagy is induced, which is consistent with the formation of liver damage. Autophagy inhibition exacerbated dasatinib-induced liver failure, suggesting that autophagy acted as a self-defense mechanism to promote survival. Oxidative stress has been shown to be an important stimulus for autophagy and hepatotoxicity. Interestingly, dasatinib increased the activity of p38, which is a critical modulator of the oxidative stress related to liver injury and autophagy. p38 silencing significantly blocked LC3-II induction and p62 reduction by dasatinib, which was accompanied by increased caspase-3 and PARP cleavage, indicating that autophagy alleviated dasatinib-induced hepatotoxicity via p38 signaling. Finally, the p38 agonist isoproterenol hydrochloride (ISO) alleviated dasatinib-induced liver failure by enhancing autophagy without affecting the anticancer activity of dasatinib. Thus, this study revealed that p38-activated autophagy promoted survival during liver injury, which may provide novel approaches for managing the clinical applications of dasatinib.