癌治療に関連した心臓障害を防ぐタンパク質の発見(Protein discovery could help prevent cancer treatment-related heart damage)

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2024-06-04 ワシントン州立大学(WSU)

ワシントン州立大学の研究によると、CDK7というタンパク質を阻害することで、一般的な抗がん剤ドキソルビシンによる心臓損傷を防げる可能性があると判明しました。CDK7を抑制することで、薬剤のがん細胞殺傷能力も向上することが示されています。この研究は動物モデルに基づいており、将来的な治療戦略の基礎を提供します。ドキソルビシンは多くのがん治療に使用されますが、心臓への毒性が問題となります。CDK7阻害剤THZ1を使用することで、心臓機能の向上と腫瘍成長の抑制が同時に達成できる可能性があります。今後の研究では、若いマウスでの長期的な効果を調べ、他の関連タンパク質も探求する予定です。

<関連情報>

サイクリン依存性キナーゼ7の阻害はドキソルビシンの心毒性を緩和し、抗癌効果を高める Inhibition of cyclin-dependent kinase 7 mitigates doxorubicin cardiotoxicity and enhances anticancer efficacy

Jingrui Chen, Jing Wei, Peng Xia, Yuening Liu, Mahder Dawit Belew, Ryan Toohill, Boyang Jason Wu, Zhaokang Cheng
Cardiovascular Research  Published:22 April 2024
DOI:https://doi.org/10.1093/cvr/cvae084

Abstract

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 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.

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 tumour growth when used in combination with DOX in an immunocompetent mouse model of breast cancer.

Conclusion
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.

癌治療に関連した心臓障害を防ぐタンパク質の発見(Protein discovery could help prevent cancer treatment-related heart damage)

Graphical Abstract

有機化学・薬学
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