Department of Pharmaceutical Sciences, Washington State University, 412 E. Spokane Falls Blvd., Spokane, WA 99202-2131, USA.
Cardiovasc Res. 2024 Jul 31;120(9):1024-1036. doi: 10.1093/cvr/cvae084.
The anthracycline family of anticancer agents such as doxorubicin (DOX) can induce apoptotic death of cardiomyocytes and cause cardiotoxicity. We previously reported that DOX-induced apoptosis is accompanied by cardiomyocyte cell cycle re-entry. Cell cycle progression requires cyclin-dependent kinase 7 (CDK7)-mediated activation of downstream cell cycle CDKs. This study aims to determine whether CDK7 can be targeted for cardioprotection during anthracycline chemotherapy.
DOX exposure induced CDK7 activation in mouse heart and isolated cardiomyocytes. Cardiac-specific ablation of Cdk7 attenuated DOX-induced cardiac dysfunction and fibrosis. Treatment with the covalent CDK7 inhibitor THZ1 also protected against DOX-induced cardiomyopathy and apoptosis. DOX treatment induced activation of the proapoptotic CDK2-FOXO1-Bim axis in a CDK7-dependent manner. In response to DOX, endogenous CDK7 directly bound and phosphorylated CDK2 at Thr160 in cardiomyocytes, leading to full CDK2 kinase activation. Importantly, inhibition of CDK7 further suppressed tumour growth when used in combination with DOX in an immunocompetent mouse model of breast cancer.
Activation of CDK7 is necessary for DOX-induced cardiomyocyte apoptosis and cardiomyopathy. Our findings uncover a novel proapoptotic role for CDK7 in cardiomyocytes. Moreover, this study suggests that inhibition of CDK7 attenuates DOX-induced cardiotoxicity but augments the anticancer efficacy of DOX. Therefore, combined administration of CDK7 inhibitor and DOX may exhibit diminished cardiotoxicity but superior anticancer activity.
蒽环类抗癌药物如多柔比星（DOX）可诱导心肌细胞凋亡并导致心脏毒性。我们之前报道过 DOX 诱导的凋亡伴随着心肌细胞细胞周期再进入。细胞周期的进展需要细胞周期蛋白依赖性激酶 7（CDK7）介导的下游细胞周期 CDK 的激活。本研究旨在确定 CDK7 是否可作为蒽环类化疗期间的心脏保护靶点。
DOX 暴露诱导小鼠心脏和分离的心肌细胞中 CDK7 的激活。心脏特异性敲除 Cdk7 可减轻 DOX 诱导的心脏功能障碍和纤维化。共价 CDK7 抑制剂 THZ1 的治疗也可预防 DOX 诱导的心肌病和细胞凋亡。DOX 处理以 CDK7 依赖性方式诱导促凋亡 CDK2-FOXO1-Bim 轴的激活。在 DOX 处理下，内源性 CDK7 直接在心肌细胞中与 CDK2 结合并磷酸化 CDK2 的 Thr160 位，导致完全激活 CDK2 激酶。重要的是，在乳腺癌免疫功能正常的小鼠模型中，与 DOX 联合使用 CDK7 抑制剂可进一步抑制肿瘤生长。
CDK7 的激活是 DOX 诱导的心肌细胞凋亡和心肌病所必需的。我们的研究结果揭示了 CDK7 在心肌细胞中促凋亡的新作用。此外，本研究表明抑制 CDK7 可减轻 DOX 诱导的心脏毒性，但增强 DOX 的抗癌疗效。因此，CDK7 抑制剂和 DOX 的联合给药可能表现出降低的心脏毒性但具有更好的抗癌活性。
