Caloric Restriction Mimetic 2-Deoxyglucose Antagonizes Doxorubicin-induced Cardiomyocyte Death by Multiple Mechanisms

Caloric restriction (CR) is a dietary intervention known to enhance cardiovascular health. The glucose analog 2-deoxy-D-glucose (2-DG) mimics CR effects in several animal models. However, whether 2-DG is beneficial to the heart remains obscure. Here, we tested the ability of 2-DG to reduce cardiomyocyte death triggered by doxorubicin (DOX, 1 μm), an antitumor drug that can cause heart failure. Treatment of neonatal rat cardiomyocytes with 0.5 mm 2-DG dramatically suppressed DOX cytotoxicity as indicated by a decreased number of cells that stained positive for propidium iodide and reduced apoptotic markers. 2-DG decreased intracellular ATP levels by 17.9%, but it prevented DOX-induced severe depletion of ATP, which may contribute to 2-DG-mediated cytoprotection. Also, 2-DG increased the activity of AMP-activated protein kinase (AMPK). Blocking AMPK signaling with compound C or small interfering RNA-mediated knockdown of the catalytic subunit markedly attenuated the protective effects of 2-DG. Conversely, AMPK activation by pharmacological or genetic approach reduced DOX cardiotoxicity but did not produce additive effects when used together with 2-DG. In addition, 2-DG induced autophagy, a cellular degradation pathway whose activation could be either protective or detrimental depending on the context. Paradoxically, despite its ability to activate autophagy, 2-DG prevented DOX-induced detrimental autophagy. Together, these results suggest that the CR mimetic 2-DG can antagonize DOX-induced cardiomyocyte death, which is mediated through multiple mechanisms, including the preservation of ATP content, the activation of AMPK, and the inhibition of autophagy.