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.
Highlights
Tyrosine kinase inhibitors are recognized as targeted therapies by exhibiting improved antitumor effects with lower toxicities than traditional chemotherapies, increasing clinical evidence suggests that they have off-target effects on non-cancerous cells, which can lead to unexpected side effects.[1]
Since dasatinib therapy has been examined in phase I/II studies of solid tumors with only modest clinical activity due to its dose limitation based on liver failure [16], we are encouraged to further assess the relationship between hepatotoxicity and antitumor activity in a xenograft mouse model bearing A549 lung cancer cells
Nude mice inoculated with A549 cells were divided into 2 groups, and it was found that 50 mg/kg dasatinib induced effective antitumor activity coupled with remarkable liver injury
Summary
Tyrosine kinase inhibitors are recognized as targeted therapies by exhibiting improved antitumor effects with lower toxicities than traditional chemotherapies, increasing clinical evidence suggests that they have off-target effects on non-cancerous cells, which can lead to unexpected side effects.[1] As a novel, oral-administrated, and multi-targeted inhibitor of the BCR-ABL and Src family kinases, dasatinib is approved for the treatment of all chronic myelogenous leukemia (CML) and Ph-positive acute lymphocytic leukemia patients resistant or intolerant to the first-line therapy.[2] hepatotoxicity is a specific concern associated with dasatinib in clinic. [3] A similar result is observed in another phase II study performed on 116 patients with CML in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC). Liver dysfunction during treatment with these medications is receiving considerable attention, and the discovery of new defenses against dasatinib-induced liver injury may www.impactjournals.com/oncotarget improve its clinical efficiency through ensuring the safety of long-term application of dasatinib
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