Elsevier

Life Sciences

Volume 93, Issue 24, 5 December 2013, Pages 913-916
Life Sciences

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The role of autophagy in doxorubicin-induced cardiotoxicity

https://doi.org/10.1016/j.lfs.2013.10.013Get rights and content

Abstract

Doxorubicin (Dox) is an effective chemotherapeutic agent, however, its use is limited by cardiotoxicity. The mechanisms causing cardiotoxicity have not been clearly elucidated, but known to involve, at least in part, oxidative stress, mitochondrial dysfunction and apoptosis. More recently, it has been suggested that dysregulation of autophagy may also play an important role in Dox-induced cardiotoxicity. Autophagy has dual functions. Under physiological conditions, autophagy is essential for optimal cellular function and survival by ridding the cell of damaged or unwanted proteins and organelles. Under pathological conditions, autophagy may be stimulated in order to protect the cell from stress stimuli or, alternatively, to contribute to cell death. Thus, appropriate regulation of autophagy can be a matter of life or death. The role of autophagy in Dox-induced cardiotoxicity has recently been explored, however, conflicting reports on the effects of Dox on autophagy and its role in cardiotoxicity exist. Most, but not all, of the studies conclude that Dox upregulates cardiac autophagy and contributes to the pathogenesis of Dox-induced toxicity. Dox may induce autophagy by suppressing the expression of GATA4 and/or S6K1, which may directly or indirectly regulate expression of essential autophagy genes such as Atg12, Atg5, Beclin1 and Bcl-2. Interestingly, the Dox-induced autophagic response may be species specific as Dox treatment has been shown to stimulate autophagy in rat models, but suppress autophagy in mouse models. Additional studies will elucidate this possibility.

Introduction

Doxorubicin (Dox) is an effective chemotherapeutic agent, however, it is well known that it is cardiotoxic (Minotti et al., 2004, Ferreira et al., 2008). The risk of cardiotoxicity increases in a dose-dependent manner and, thus, the use of doxorubicin in cancer patients is limited (Chatterjee et al., 2010). The mechanisms of toxicity have not been clearly elucidated, but known to involve, at least in part, oxidative stress, mitochondrial dysfunction and apoptosis (Childs et al., 2002, Pointon et al., 2010, Zhang et al., 2012). More recently, it has been suggested that dysregulation of autophagy may also play a contributing role in Dox-induced cardiotoxicity (Lu et al., 2009, Kawaguchi et al., 2012).

Autophagy has been shown to have dual functions. Autophagy can enhance cellular function and survival by degrading damaged or unwanted proteins and organelles, and by inhibiting apoptosis (Gottlieb et al., 2009). Alternatively, autophagy can induce cell death (Rubinstein and Kimchi, 2012). Thus, appropriate regulation of autophagy can be a matter of life or death which will depend on the stress stimuli and cellular environment. Under physiologic basal conditions, autophagy is regarded as a protective process ridding the cell of potentially harmful debris. Under pathological conditions, enhanced autophagy has been shown to have a protective role in some cardiac disease states, such as ischemic preconditioning, while it is harmful in others, such as cardiac hypertrophy (Sciarretta et al., 2012).

The role of autophagy in Dox-induced cardiotoxicity has recently been explored, however, conflicting reports on the effects of Dox on autophagy and its role in cardiotoxicity exist. Thus, the aim of this review is to describe the core autophagy machinery, summarize current knowledge and to elucidate the role of autophagy in Dox-induced cardiotoxicity.

Section snippets

Overview of the core autophagy machinery

Three forms of autophagy have been identified: macroautophagy, microautophagy, and chaperone-mediated autophagy (Glick et al., 2010). All three forms result in degradation of cargo (e.g. cytosolic proteins or organelles) by the lysosome, however, the mechanism of delivery to the lysosome differs. Macroautophagy requires the formation of a double membrane autophagosome to deliver the cargo to the lysosome. Microautophagy constitutes the direct uptake of cargo by the lysosome and

Doxorubicin-induced autophagy

Several studies have shown that Dox treatment affects autophagy in vitro and in vivo. Some have shown that Dox treatment increases autophagy and some have shown that Dox decreases autophagy. Since autophagy has dual functions in life and death of cardiomyocytes, several investigators have employed chemical means of manipulating autophagy to elucidate its role in Dox-induced cardiotoxicity. However, it is important to note that many of the most commonly used chemical modulators of autophagy have

Conclusions

Autophagy has dual functions. Under physiological conditions, autophagy is essential for optimal cellular function and survival by ridding the cell of damaged or unwanted macromolecules and organelles. Under pathological conditions, autophagy may be stimulated in order to protect the cell from stress stimuli or to contribute to cell death. As far as its role in Dox-induced cardiotoxicity, most studies conclude that Dox upregulates cardiac autophagy. Moreover, attenuation of autophagy confers a

Conflict of interest statement

The author declares no conflict of interest.

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