与伊马替尼和索拉非尼在离体大鼠心脏纤维和心肌细胞 H9c2 细胞系中的线粒体毒性相关

Mitochondrial toxicity associated with imatinib and sorafenib in isolated rat heart fibers and the cardiomyoblast H9c2 cell line.

Keywords：imatinib; sorafenib; cardiotoxicity; electron transfer system; reactive oxygen species; glutathione; apoptosis

关键词：伊马替尼；索拉非尼；心脏毒性; 电子转移系统；活性氧；谷胱甘肽；细胞凋亡
作者：Bouitbir J , Panajatovic MV , Kraehenbuehl S
出版期刊：《Int. J. Mol. Sci. 》（ 2022年）

Abstract：

Tyrosine kinase inhibitors (TKIs) are associated with cardiac toxicity, which may be caused by mitochondrial toxicity. The underlying mechanisms are currently unclear and require further investigation. In the present study, we aimed to investigate in more detail the role of the enzyme Complexes of the electron transfer system (ETS), mitochondrial oxidative stress, and mechanisms of cell death in cardiac toxicity associated with imatinib and sorafenib. Cardiac myoblast H9c2 cells were exposed to imatinib and sorafenib (1 to 100 µM) for 24 h. Permeabilized rat cardiac fibers were treated with both drugs for 15 min. H9c2 cells exposed to sorafenib for 24 h showed a higher membrane toxicity and ATP depletion in the presence of galactose (favoring mitochondrial metabolism) compared to glucose (favoring glycolysis) but not when exposed to imatinib. Both TKIs resulted in a higher dissipation of the mitochondrial membrane potential in galactose compared to glucose media. Imatinib inhibited Complex I (CI)- and CIII-linked respiration under both conditions. Sorafenib impaired CI-, CII-, and CIII-linked respiration in H9c2 cells cultured with glucose, whereas it inhibited all ETS complexes with galactose. In permeabilized rat cardiac myofibers, acute exposure to imatinib and sorafenib decreased CI- and CIV-linked respiration in the presence of the drugs. Electron microscopy showed enlarged mitochondria with disorganized cristae. In addition, both TKIs caused mitochondrial superoxide accumulation and decreased the cellular GSH pool. Both TKIs induced caspase 3/7 activation, suggesting apoptosis as a mechanism of cell death. Imatinib and sorafenib impaired the function of cardiac mitochondria in isolated rat cardiac fibers and in H9c2 cells at plasma concentrations reached in humans. Both imatinib and sorafenib impaired the function of enzyme complexes of the ETS, which was associated with mitochondrial ROS accumulation and cell death by apoptosis.

文章摘要：

酪氨酸激酶抑制剂 (TKI) 与心脏毒性有关，这可能是由线粒体毒性引起的。潜在的机制目前尚不清楚，需要进一步研究。在本研究中，我们旨在更详细地研究电子转移系统 (ETS) 酶复合物、线粒体氧化应激以及细胞死亡在与伊马替尼和索拉非尼相关的心脏毒性中的作用。将心脏成肌细胞 H9c2 细胞暴露于伊马替尼和索拉非尼（1 至 100 µM）24 小时。用两种药物处理透化的大鼠心肌纤维 15 分钟。与葡萄糖（有利于糖酵解）相比，暴露于索拉非尼 24 小时的 H9c2 细胞在半乳糖（有利于线粒体代谢）存在下表现出更高的膜毒性和 ATP 消耗，但在暴露于伊马替尼时则不然。与葡萄糖介质相比，两种 TKI 均导致半乳糖中线粒体膜电位的耗散更高。伊马替尼在两种情况下均抑制复合物 I (CI) 和 CIII 相关的呼吸。索拉非尼在用葡萄糖培养的 H9c2 细胞中损害 CI-、CII-和 CIII-相关的呼吸，而它抑制所有 ETS 与半乳糖的复合物。在透化大鼠心肌肌纤维中，急性暴露于伊马替尼和索拉非尼在药物存在的情况下降低了 CI 和 CIV 相关的呼吸。电子显微镜显示线粒体增大，嵴杂乱无章。此外，两种 TKI 均引起线粒体超氧化物积累并减少细胞 GSH 池。两种 TKI 均诱导 caspase 3/7 活化，表明细胞凋亡是细胞死亡的一种机制。伊马替尼和索拉非尼在人血浆浓度达到时，会损害离体大鼠心脏纤维和 H9c2 细胞中心脏线粒体的功能。伊马替尼和索拉非尼都损害了 ETS 酶复合物的功能，这与线粒体 ROS 积累和细胞凋亡引起的细胞死亡有关。

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