Aims 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-reentry. 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. Methods and Results 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 tumor growth when used in combination with DOX in an immunocompetent mouse model of breast cancer. Conclusions 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.

中文翻译：

---

抑制 CDK7 可减轻阿霉素心脏毒性并增强抗癌功​​效

目的 蒽环类抗癌药物家族，如阿霉素 (DOX)，可诱导心肌细胞凋亡并引起心脏毒性。我们之前报道过 DOX 诱导的细胞凋亡伴随着心肌细胞细胞周期重入。细胞周期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 是否可以作为蒽环类化疗期间心脏保护的靶标。方法和结果 DOX 暴露诱导小鼠心脏和分离的心肌细胞中 CDK7 激活。 Cdk7 的心脏特异性消融可减轻 DOX 诱导的心脏功能障碍和纤维化。使用共价 CDK7 抑制剂 THZ1 治疗还可以预防 DOX 诱导的心肌病和细胞凋亡。 DOX 治疗以 CDK7 依赖性方式诱导促凋亡 CDK2-FOXO1-Bim 轴的激活。响应 DOX，内源性 CDK7 直接结合心肌细胞中 Thr160 位点的 CDK2 并使其磷酸化，从而导致 CDK2 激酶完全激活。重要的是，在免疫活性小鼠乳腺癌模型中，与 DOX 联合使用时，CDK7 的抑制进一步抑制了肿瘤生长。结论 CDK7的激活是DOX诱导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 在心肌细胞中的新的促凋亡作用。此外，这项研究表明，抑制 CDK7 可以减轻 DOX 诱导的心脏毒性，但增强 DOX 的抗癌功效。因此，CDK7抑制剂和DOX联合给药可能表现出降低的心脏毒性但具有优异的抗癌活性。