College of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada.
Cardiovasc Toxicol. 2020 Aug;20(4):380-389. doi: 10.1007/s12012-020-09565-7.
The anticancer drug dasatinib (Sprycel) is a BCR-ABL1-targeted tyrosine kinase inhibitor used in treating chronic myelogenous leukemia that has been shown in clinical trials to display cardiovascular toxicities. While dasatinib potently inhibits BCR-ABL1, it is not a highly selective kinase inhibitor and may have off-target effects. A neonatal rat cardiac myocyte model was used to investigate potential mechanisms by which dasatinib damaged myocytes. The anthracycline cardioprotective drug dexrazoxane was shown to be ineffective in preventing dasatinib-induced myocyte damage. Dasatinib treatment increased doxorubicin accumulation in myocytes and doxorubicin-induced myocyte damage, likely through its ability to bind to one or more ABC-type efflux transporters. Dasatinib induced myocyte damage either after a brief treatment that mimicked the clinical situation, or more potently after continuous treatment. Dasatinib slightly induced apoptosis in myocytes as evidenced by increases in caspase-3/7 activity. Dasatinib treatment reduced pERK levels in myocytes most likely through inhibition of RAF, which dasatinib strongly inhibits. Thus, inhibition of the RAF/MEK/ERK pro-survival pathway in the heart may be, in part, a mechanism by which dasatinib induces cardiovascular toxicity.
抗癌药物达沙替尼（Sprycel）是一种 BCR-ABL1 靶向酪氨酸激酶抑制剂，用于治疗慢性粒细胞白血病，临床试验表明其具有心血管毒性。虽然达沙替尼能强力抑制 BCR-ABL1，但它不是一种高选择性的激酶抑制剂，可能具有非靶向作用。使用新生大鼠心肌细胞模型研究了达沙替尼损伤心肌细胞的潜在机制。阿霉素类心脏保护药物右雷佐生被证明不能有效预防达沙替尼引起的心肌细胞损伤。达沙替尼治疗增加了心肌细胞中的多柔比星蓄积和多柔比星引起的心肌细胞损伤，这可能是通过其与一种或多种 ABC 型外排转运蛋白结合的能力。达沙替尼在模拟临床情况的短暂治疗后或在持续治疗后更强烈地诱导心肌细胞损伤。达沙替尼治疗轻微诱导心肌细胞凋亡，这一点可以通过 caspase-3/7 活性的增加来证明。达沙替尼治疗降低了心肌细胞中 pERK 的水平，这很可能是通过抑制 RAF 实现的，而 RAF 是达沙替尼强烈抑制的。因此，抑制心脏中的 RAF/MEK/ERK 生存途径可能是达沙替尼引起心血管毒性的部分机制。
