Abstract 5602: Cyclin D2- mediated cardiomyocyte cell cycle activity reverses doxorubicin-induced cardiotoxicity.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Doxorubicin (DOX) is an effective anticancer agent which also induces acute and chronic cardiotoxicities. We have generated a juvenile mouse model to study DOX-induced cardiotoxicity in children. Cardiomyocyte apoptosis with an ensuing loss of myocardial function is observed in this model. Here, we hypothesize that activation of cardiomyocyte cell cycle protects against DOX-induced cardiotoxicity. Methods: Two week old MHC-cylin D2 (D2) mice and their non-transgenic (NON-TXG) littermates were given weekly DOX injections for 5 weeks (25 mg/kg total dose). Animals were studied 1 week (acute stage) or 13 weeks (late stage) after the last DOX injection. Cardiac function was measured with echocardiography and cardiomyocyte (CM) cell cycle was quantified using a tritiated thymidine incorporation assay. Results: Our results showed that CM cell cycle was increased in D2 mice as compared to NON-TXG mice (thymidine positive CM nuclei, 0.03±0.01% vs. 0.002±0.002 in acute stage, p 0.05), whereas in the presence of CM cell cycle activity, cardiac function improved in late stage vs. acute stage (FS = 60.1±1.3% vs. 47.1±3.3%, p<0.01). CM apoptosis (0.02±0.01/mm2 vs. 0.05±0.01/mm2, p<0.01) and fibrosis (6.2±0.9% vs. 12.0±1.7%, p<0.01) was reduced in D2 mice as compared to NON-TXG mice in late stage. Conclusion: For the first time, our data suggest activation of CM cell cycle in adult mice reverses DOX-induced cardiotoxicity. Citation Format: Wuqiang Zhu, Mark H. Soonpaa, Wenjun Zhang, Weinian Shou, Mark Payne, Loren J. Field. Cyclin D2- mediated cardiomyocyte cell cycle activity reverses doxorubicin-induced cardiotoxicity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5602. doi:10.1158/1538-7445.AM2013-5602