酪氨酸激酶抑制剂索拉非尼造成代谢型心脏毒性的分子机理

酪氨酸激酶抑制剂是一类临床上广泛使用的抗肿瘤药物，然而其中一些会造成严重的心脏毒性，缺乏有效的治疗方法。毒性机理是由药物对其靶点及下游信号通路的急性作用，和药物脱靶地慢性作用共同决定的。我们发现一种毒性较高的酪氨酸激酶抑制剂索拉非尼脱靶地抑制线粒体呼吸链，并造成糖酵解的增加以代偿能量损失，而长期的处理导致AMPKα2表达下降，ATP水平降低和细胞收缩功能丧失。我们推测索拉非尼造成的心脏毒性是由于其对能量代偿的AMPK的抑制。本研究重点探讨：1.AMPKα2的表达量与索拉非尼引起的心脏毒性成负相关；2.索拉非尼的心脏毒性是由AMPKα2介导的；3.索拉非尼通过E2F调控AMPKα2表达；4.干预索拉非尼调控AMPKα2表达机制以减轻心脏毒性的方法。研究索拉非尼心脏毒性的分子机制，有助于找到可能降低毒性的治疗靶点，提升对心肌代谢调控机制的理解，为发展出检测代谢型心脏毒性的临床前方法打下基

Tyrosine kinase inhibitors (TKIs) are a class of anti-tumor drugs widely used in clinic, but some of them cause severe cardiotoxicity. Effective therapies targeted at molecular mechanisms of cardiotoxicity are still lacking. Current research on TKI-induced cardiotoxicity focuses on acute and on-target effects of the drugs, but largely ignores chronic and off-target effects. We found that a highly cardiotoxic TKI, Sorafenib, inhibited mitochondrial respiration as a major off-target and caused an increase in anaerobic glycolysis to compensate for ATP loss. But long-term drug treatment led to a significant reduction in AMPKα2 expression and in ATP levels, as well as defective cellular contraction. We hypothesize that molecular mechanism of Sorafenib-induced cardiotoxicity is due to inhibition of AMPK on energy metabolic compensation. Therefore, the main aims of this proposal are: 1. Confirm that Sorafenib-induced cardiotoxcity is associated with decreased expression of AMPKα2; 2. Prove that Sorafenib-induced metabolic cardiotoxicity is mediated by AMPKα2; 3. Investigate how Sorafenib acts through E2F transcriptional factors to regulate AMPKα2 expression; 4. Find ways to reduce cardiotoxicity by targeting the regulation of AMPKα2 expression. Research on molecular mechanisms of metabolic cardiotoxicity induced by Sorafenib will help us find potential drug targets to remedy the disease, deepen our understanding of regulation of energy metabolism in cardiac muscle cells, and provide theoretical support on developing non-clinical models to detect metabolic cardiotoxicity.