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-Dglucose (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 M), 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.

Resveratrol Attenuates Doxorubicin-Induced Cardiomyocyte Death via Inhibition of p70 S6 Kinase 1-Mediated Autophagy

“…NRCs were pretreated with resveratrol (10 M) for 12 h and then Resveratrol Inhibits Doxorubicin Cardiotoxicity exposed to DOX (1 M) for another 18 h. The lysosomal inhibitor BFA (50 nM) was added 6 h before the cells were examined for GFP-LC3 dots (AVs) under a confocal microscope. In line with previous reports Kobayashi et al, 2010;Chen et al, 2011), DOX triggered the formation of numerous AVs as indicated by the GFP-LC3 dots, which was further increased by BFA treatment ( Fig. 2A), suggesting that DOX accelerated autophagic flux in cardiomyocytes.…”

“…DOX can induce autophagy in cardiomyocytes, which is a major mechanism of DOX cardiotoxicity Kobayashi et al, 2010;Chen et al, 2011). Therefore, we tested whether resveratrol could inhibit DOXinduced autophagy.…”

“…For example, high-level autophagy during reperfusion is harmful (Matsui et al, 2007), and diphtheria toxin triggers autophagy, leading to heart failure in mice (Akazawa et al, 2004). Likewise, DOX can induce autophagy in cardiomyocytes, which is detrimental in nature because inhibiting autophagy with chemical or genetic approaches dramatically attenuates DOX-induced cardiomyocyte death Kobayashi et al, 2010;Chen et al, 2011). Thus, a potential therapeutic strategy to reducing DOX cardiotoxicity is to suppress DOX-induced autophagy.…”

Can short-term fasting protect against doxorubicin-induced cardiotoxicity?

“…Thus the role of autophagy in Dox-induced cardiotoxicity, whether protective or pathological, is still under question. Therefore, the underlying mechanism(s) of fasting-induced cardioprotection against Dox remains to be determined and is likely due to a combination of mechanisms [30] .…”

“…Microscopy revealed attenuation of LV dilatation, myocardial atrophy, and fibrosis [29] . In vitro, a caloric restriction mimetic, 2-deoxyglucose (2-DG), was shown to exhibit cardioprotective properties against Dox using neonatal rat cardiomyocytes isolated from 0-2 d old Harlan Sprague-Dawley rat neonates [30] . Thus, the literature supports that fasting may be an effective regimen to protect against Dox-induced cardiotoxicity.…”