MinireviewThe role of autophagy in doxorubicin-induced cardiotoxicity
Graphical abstract
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.
References (20)
- et al.
Caloric restriction mimetic 2-deoxyglucose antagonizes doxorubicin-induced cardiomyocyte death by multiple mechanisms
J Biol Chem
(2011) - et al.
Distinct autophagosomal–lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest
Mol Cell
(2011) - et al.
Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death
J Biol Chem
(2010) - et al.
Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure
Int J Cardiol
(2009) - et al.
Autophagy upregulation promotes survival and attenuates doxorubicin-induced cardiotoxicity
Biochem Pharmacol
(2013) - et al.
Doxorubicin cardiomyopathy
Cardiology
(2010) - et al.
Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio
Cancer Res
(2002) - et al.
Effects of doxorubicin cancer therapy on autophagy and the ubiquitin-proteasome system in long-term cultured adult rat cardiomyocytes
Cell Tissue Res
(2012) - et al.
Anthracycline-induced cardiotoxicity
Cardiovasc Hematol Agents Med Chem
(2008) - et al.
Autophagy: cellular and molecular mechanisms
J Pathol
(2010)