HMGB1-mediated necroptosis contributes to dasatinib-induced cardiotoxicity
Background:Dasatinib shows remarkable activity in imatinib-refractory chronic myelogenous leukemia(CML)and Philadelphia chromosome positive acute lymphoblastic leukaemia(Ph+ALL).However,the severe cardiovascular toxicity limits its clinical applications.The underlying mechanism of dasatinib-induced cardiotoxicity is still elusive.Methods and results:we first report that dasatinib could directly induce cardiomyocytes death,as analyzed by the sulforhodamine B(SRB)assay.This type of cardiomyocytes death was by the necroptosis pathway rather than apoptosis,as determined by using flow cytometry to characterize the mode of dasatinib-induced cell death.Inhibition of RIP1 activity and knockdown of RIP3 expression can block dasatinib-evoked cardiotoxicity,which further confirmed the involvement of necroptosis.Moreover,we found that the classic substrates of RIP3,mixed lineage kinase domain-like protein(MLKL)and Ca2+-calmodulin-dependent protein kinase Ⅱ(CaMKⅡ)were not involved in dasatinib-induced cardiomyocytes necroptosis.Unlike the inflammation-associated necroptosis,dasatinib-triggered necroptosis was dependent on intracellular instead of secreted HMGB1 protein.Conclusion:We uncovered dasatinib-induced cardiotoxicity via leading cardiomyocytes to HMGB1-mediated necroptosis.Theses results suggest that suppression of HMGB1 constitutes a viable strategy for dasatinib-based cancer therapy.Dasatinib shows remarkable activity against imatinib-refractory chronic myelogenous leukemia(CML)and Philadelphia chromosome positive acute lymphoblastic leukemia(Ph+ALL).However,severe cardiovascular toxicity limits the clinical applications of dasatinib.The underlying mechanism of dasatinib-induced cardiotoxicity is still elusive.Here,Collectively,our study revealed dasatinib-induced cardiotoxicity acts via leading cardiomyocytes to HMGB1-mediated necroptosis,indicating a viable strategy for dasatinib-based cancer therapy.
dasatinib cardiotoxicity,necroptosis HMGB1
Ying Jin Zhifei Xu Hao Yan Bo Yang Qiaojun He Peihua Luo
Institute of Pharmacology&Toxicology,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China
国内会议
杭州
英文
105-113
2018-07-03（万方平台首次上网日期，不代表论文的发表时间）