title: Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms.
abstract: 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.
authors.affiliation: Cardiovascular Health Research Center, Sanford Research/University of South Dakota, Sioux Falls, South Dakota 57104, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Xianmin
authors.initials: X
authors.lastname: Xu
authors.forename: Satoru
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Derek
authors.initials: D
authors.lastname: Timm
authors.forename: Tyler
authors.initials: T
authors.lastname: Jepperson
authors.forename: Qiangrong
authors.initials: Q
authors.lastname: Liang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D031204:Caloric Restriction; D016923:Cell Death / Q000187:drug effects*; D019610:Cytoprotection / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D004317:Doxorubicin / Q000009:adverse effects* / Q000037:antagonists & inhibitors*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004317:Doxorubicin; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D055372:AMP-Activated Protein Kinases