Because doxorubicin (DOX)-containing chemotherapy causes left ventricular (LV) dysfunction and remodeling that can progress to heart failure, strategies to alleviate DOX cardiotoxicity are necessary to improve health outcomes of patients surviving cancer. Although clinical evidence suggests that aerobic exercise training (ET) can prevent cardiotoxicity in patients undergoing DOX chemotherapy, the physiological mechanisms involved have not been extensively studied, nor is it known whether compounds [such as resveratrol (RESV)] have similar beneficial effects. With the use of a murine model of chronic DOX exposure, this study compared the efficacy of modest ET to RESV treatment on exercise performance, LV remodeling, and oxidative stress resistance. Mice were divided into four groups that received saline, DOX (8 mg/kg ip, one time per week), DOX + RESV (4 g/kg diet, ad libitum), and DOX + ET (45 min of treadmill exercise, 5 days/wk) for 8 wk. LV function and morphology were evaluated by in vivo echocardiography. DOX caused adverse LV remodeling that was partially attenuated by modest ET and completely prevented by RESV. These effects were paralleled by improvements in exercise performance. The cardioprotective properties of ET and RESV were associated with reduced levels of atrial natriuretic peptide and the lipid peroxidation by-product, 4-hydroxy-2-nonenal. In addition, ET and RESV increased the expression of cardiac sarcoplasmic/endoplasmic reticulum calcium-ATPase 2a, superoxide dismutase, mitochondrial electron transport chain complexes, and mitofusin-1 and -2 in mice administered DOX. Compared with modest ET, RESV more effectively prevented DOX-induced LV remodeling and was associated with the reduction of DOX-induced oxidative stress. Our findings have important implications for protecting patients against DOX-associated cardiac injury.

Resveratrol differentially regulates pathological and physiological cardiac hypertrophy. Resveratrol dose selectively inhibits pathological cardiac signaling pathways. Resveratrol inhibits NFAT-dependent transcription. At low concentrations, effects of resveratrol are AMPK-independent. Resveratrol may be used to selectively treat pathological cardiac hypertrophy.

Background: It is well-established that doxorubicin (DOX)-containing chemotherapy causes progressive cardiomyopathy clinically manifest as decreased left ventricular ejection fraction (LVEF). The effects of DOX on the other organ components of oxygen (O2) transport and utilization that govern global aerobic reserve capacity are poorly characterized. Methods and Results: To test our research questions, we established a mouse model of DOX in which female mice were subjected to DOX (8mg.kg.wk-1) or placebo (CON) (0.9% saline) for 4 weeks. Transthoracic echocardiography was performed to assess left ventricular wall thickness, volumes and LVEF, determined from M-mode tracings at baseline and 8 weeks. As expected, LV systolic volumes were higher and fractional shortening and LVEF were lower in the DOX group compared to CON after 8 weeks (p's <0.05). There was no change in effective arterial elastance (i.e. peripheral resistance, total lumped vascular compliance and characteristic impedance) following DOX however these mice had significantly decreased expression of proteins responsible for oxidative phosphorylation / mitochondrial biogenesis in the solelus muscle relative to CON mice (p<0.05). Injury to O2 transport organs led to significant reductions in global aerobic capacity (as measured by time to exhaustion on a motorized treadmill) in DOX compared with CON animals (p<0.05). Next, we tested whether aerobic training could prevent DOX-induced injury. Mice were subjected treadmill running, 5 d.wk-1, 18m.min-1, 45 mins/session for 8 wks during concurrent DOX (8mg.kg.wk-1) therapy (DOX+AT), DOX (8mg.kg.wk-1) only, or CON (0.9% saline). DOX-induced injury was completely abrogated by chronic aerobic training, which prevented injury in all organ components of O2 transport / utilization cumulating in preserved aerobic capacity. In patients with newly diagnosed operable breast cancer (n=20), DOX-containing chemotherapy caused a significant decline in aerobic capacity (p<0.05) despite normal LVEF and endothelial function. Supervised aerobic training completely averted this effect. Conclusions: Our findings have important implications for the identification and protection against DOX-induced acute and late-occurring injury as well as optimizing therapeutic dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5024. doi:10.1158/1538-7445.AM2011-5024

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