Abstract 3008: Effect of exercise on acute and late onset Doxorubicin-induced cardiotoxicity
Authors: Wang Fei , Schadler Keri , Chandra Joya , Kleinerman Eugenie S. 
Published: August 2018

Abstract
Introduction Doxorubicin (Dox)-induced cardiotoxicity interferes with QOL and longevity in childhood cancer survivors. We investigated whether exercise during or after Dox can reduce acute and late onset cardiotoxicity without inhibiting efficacy. Methods Exercise during Dox and acute cardiotoxicity: 4 week old nude mice were injected with A673 Ewing's sarcoma cells subcutaneously. When tumors reached 30-50mm mice were divided into 4 groups (8 mice/group): Control (saline, no exercise); Dox alone ( 2.5mg/kg 2x/week for 2 weeks); Exercise (treadmill running, 45min/day @ 12m/min 5days/week); Dox + Exercise. Tumor growth was quantified. Heart function was evaluated using echocardiography before and after Dox. We evaluated Ejection Fraction (EF), Fractional Shortening (FS), left ventricular posterior wall diameter (LVPW) in diastole and systole, and left ventricular internal diameter (LVID) in diastole and systole. Blood was collected to assess ROS levels in PBMCs and mice were euthanized 24 h after therapy. Heart Weight/Tibial Length (HW/TL) was determined. Heart sections were analyzed by WGA & H&E to assess histology and morphology; IHC to assess vessel morphology using CD31 and α-SMA; Masson's Trichrome to access deposition of collagen in heart tissues and transmission electron micrograph (TEM) to assess autophagy, vascular pericytes and endothelial cells. Exercise after Dox and long-term cardiotoxicity: 4 groups (8mice/group): Control (no Dox, no exercise); Dox alone-no exercise; Exercise; Dox then exercise after Dox for 14 weeks. For all groups heart function was evaluated by echo as above before and after Dox and then every 2 weeks for 14 weeks. Heart sections were analyzed as above. Results Exercise during therapy did not inhibit Dox efficacy. Dox induced a significant decrease in cardiac EF%, FS% and HW/TL ratio and increased ROS in PBMCs. Exercise during therapy inhibited these effects. Dox decreased cardiac vascular pericytes and endothelial cells and induced abnormal mitochondria, vacuolization and increased autophagosomes in the heart. These changes were not seen in the Dox+exercise mice. Exercise initiated after Dox also inhibited the late effects of Dox using the same echo and tissue evaluations. Additional there was a significant decrease in LVPW in diastole (but not in systole) 14 weeks after Dox. This was not seen when exercise was initiated after therapy. Conclusion Exercise prevented both the acute and late cardiotoxicity induced by Dox without inhibiting efficacy. Therefore, exercise interventions have the potential to decrease cardiac morbidity, improve cardiac health and the QOL for childhood cancer survivors. Diastolic function is also important in heart failure. While systolic function is typically monitored in children receiving Dox, our data suggest that Dox-induced diastolic dysfunction precedes systolic dysfunction and perhaps can be used as an early marker of cardiotoxicity.
Citation Format: Fei Wang, Keri Schadler, Joya Chandra, Eugenie S. Kleinerman. Effect of exercise on acute and late onset Doxorubicin-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3008.