Molecular mechanism of doxorubicin-induced cardiomyopathy – An update

doi:10.1016/j.ejphar.2017.10.043

European Journal of Pharmacology

Volume 818, 5 January 2018, Pages 241-253

https://doi.org/10.1016/j.ejphar.2017.10.043 Get rights and content

Abstract

Doxorubicin is utilized for anti-neoplastic treatment for several decades. The utility of this drug is limited due to its side effects. Generally, doxorubicin toxicity is originated from the myocardium and then other organs are also ruined. The mechanism of doxorubicin is intercalated with the DNA and inhibits topoisomerase 2. There are various signalling mechanisms involved in doxorubicin cardiotoxicity. First and foremost, the doxorubicin-induced cardiotoxicity is due to oxidative stress. Cardiac mitochondrial damage is supposed after few hours following the revelation of doxorubicin. This has led important new uses for the mechanism of doxorubicin-induced cardiotoxicity and novel avenues of investigation to determine better pharmacotherapies and interventions for the impediment of cardiotoxicity. The idea of this review is to bring up to date the recent findings of the mechanism of doxorubicin cardiomyopathies such as calcium dysregulation, endoplasmic reticulum stress, impairment of progenitor cells, activation of immune, ubiquitous system and some other parameters.

Introduction

Doxorubicin or Adriamycin® or Doxil® is most commonly used an effective chemotherapeutic drug for the treatment of a wide range of cancers including both the solid and hematogenous cancers since 1969 (Damiani et al., 2016). This antibiotic was first discovered from a mutated strain of Streptomyces peucetius. The clinical utility of this drug is limited for its side effects especially, cardiotoxicity when it exceeds the cumulative dosage of 400–700 mg/m² for adults and 300 mg/m² in the cases of children. Upon crossing the mentioned thresholds, the chances of developing cardiotoxicity increases, with 400 mg/m² there is a 5% incidence of cardiotoxicity, with 550 mg/m² 26% risk, and with 700 mg/m², there is a risk as high as 48% (Li and Hill, 2014). Doxorubicin is biphasic in nature depends on the concentration of it (Ondrias et al., 1990). Determination of acute toxicity within two or 3 days of drug administration and chronic cardiotoxicity found in several weeks or even several months after drug administration. The cardiotoxicity could be an arrhythmia, cardiomyopathy, left ventricular dysfunction and congestive heart failure (Mitry and Edwards, 2016). Doxorubicin acquaintances robustly with cellular nuclei and intercalate with deoxyribonucleic acid (DNA) bases to mediate doxorubicin-DNA complexes, ensuing in cell demise (Cheung et al., 2015, Trouet and Deprez-De Campeneere, 1979). Doxorubicin - DNA intercalation is connected with double-strand DNA breakage and mitotic catastrophe generation (Eom et al., 2005). Doxorubicin mediates dsDNA breakage through reticence of Top2β (Topoisomerase 2-beta), and knockout of Top2β gene in mice displayed a delay in the propensity to doxorubicin-induced cardiomyocyte death (Zhang et al., 2012). Reactive oxygen species (ROS) apparently plays a key role in doxorubicin-induced cardiotoxicity. However, the precise mechanism of doxorubicin-induced cardiotoxicity is still elusive. The other mechanism contributes to doxorubicin cardiotoxicity are iron regulatory protein, nitric oxide (NO) release, Mitochondrial dysfunction, impaired adenosine triphosphate (ATP) level, hampered cardiac progenitor cells, calcium dysregulation, inflammatory mediators, endothelial dysfunction, activation of ubiquitin protease system, autophagy and cell death. Though a number of mechanisms have been shown to be involved in cardiotoxicity the exact mechanism is indistinct. This review is aimed at comprehending the cellular and molecular mechanisms by which doxorubicin induces the catastrophe in cardiomyocytes leading to heart failure. Spotlight more on the cellular and molecular mechanism of doxorubicin on the myocardium with the rationale of innovative copious delineating the essential molecular mechanisms that encourage cardiotoxicity.

Section snippets

Oxidative stress associated doxorubicin-induced cardiomyopathy – molecular consequences

Oxidative stress is one of the major effects of doxorubicin-induced cardiotoxicity. Oxidative stress is the imbalance between the production of reactive oxygen species, reactive nitrogen species (RNS) and intrinsic antioxidant mechanisms. The reactive oxygen species, reactive nitrogen species produced within the cardiomyocytes are not effectively removed/neutralized by the inherent antioxidant mechanisms of the cells (Tham et al., 2015). When the cumulative dosage of doxorubicin exceeds 500 mg/m²

Structural changes in sub-cellular organelles of myocardium

Doxorubicin-induced cardiotoxicity involves changes in the ultrastructure of subcellular organelles of cardiomyocytes. The changes in ultrastructure of sub-cellular organelles includes swelling of mitochondria, cytoplasmic vacuolization, myofibrillar loss (Singal et al., 2000a), increase in the number of lysosomes (Minotti et al., 2004), disruption of cristae in mitochondria (Ascensão et al., 2005), myocyte disruption, fibrosis (Bristow et al., 1981; Torti et al., 1986; Billingham et al., 1978

Immune response, oxidative stress, and tissue injury

Doxorubicin treatment induces the immune system to release a variety of cytokines. The Further it stops the natural killer (NK) cell activity, stimulates the responses of cytotoxic T lymphocytes (CTL) and decreases the differentiation of macrophages. Collective changes in an immune cell affect the cardiac function during doxorubicin treatment (Ehrke et al., 1984, Haskill, 1981, Maccubbin et al., 1992).

Toll-like receptors (TLR) plays an important role in pathologic changes induced by

Apoptosis

Under pathological conditions such as infracted and reperfused myocardium, diabetes, left ventricular dysfunction and hypertrophy apoptosis occurs along with necrosis. (Freude et al., 2000, Guerra et al., 1999, Sam et al., 2000, Tea et al., 1999, Zhou et al., 2000). Oxidative stress results in the release of cytochrome c through voltage-dependent anion channels (VDAC) and activation of caspase 3 in mitochondria leads to apoptosis in the myocardium. The result of apoptosis is increased by b-cell

Role of progenitor cells during cardiac injury

The heart is considered as a terminally differentiated organ, but still, it has some capacity to repair it after some injury by progenitor cells such as bone marrow progenitor cell(BMPCs) and cardiac progenitor cells (CPCs). Doxorubicin has been shown to impair the viability of clonogenic c-kit positive CPCs in vitro. Doxorubicin induces apoptosis of CPCS and prevents differentiating into myocytes. Doxorubicin also reduces the endothelial cardiac repair and also in case of cardiac lineage cells

Conclusion

Doxorubicin brings about a cure efficiently for a variety of cancer types, but its rigorous side effects can also be lethal. Mechanisms of doxorubicin-mediated cardiomyopathy are complicated and multi-factorial. The pathophysiology of doxorubicin cardiomyopathy is predominantly determined by oxidative stress. This oxidative stress is a disproportion between the oxidant and antioxidant. There are different mechanisms involved in doxorubicin-induced cardiomyopathy but the outcome is cell death

Acknowledgments

This study was financially supported by DST-SERB, Government of India, and Project file no. SB/LS/YS-99/2013. The authors would also like to thank the management of VIT University and Kalasalingam University for providing the facilities to carry out this work. The author Kaviyarasi Renu is grateful to VIT University for providing the financial assistance during this tenure.

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¹: Equal contribution for the corresponding author.

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Molecular mechanism of doxorubicin-induced cardiomyopathy – An update

Abstract

Introduction

Section snippets

Oxidative stress associated doxorubicin-induced cardiomyopathy – molecular consequences

Structural changes in sub-cellular organelles of myocardium

Immune response, oxidative stress, and tissue injury

Apoptosis

Role of progenitor cells during cardiac injury

Conclusion

Acknowledgments

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The role of renin-angiotensin system antagonists in the prevention of doxorubicin and trastuzumab-induced cardiotoxicity

Cardiovasc. Ultrasound

Insights into mechanisms of doxorubicin cardiotoxicity

J. Phys. Pharm. Adv.

UVRAG deficiency exacerbates doxorubicin-induced cardiotoxicity

Sci. Rep.

L-carnitine prevents doxorubicin-induced apoptosis of cardiac myocytes: the role of inhibition of ceramide generation

FASEB J.

Essential role of GATA-4 in cell survival and drug-induced cardiotoxicity

Proc. Natl. Acad. Sci. USA

Acute doxorubicin cardiotoxicity involves cardiomyocyte apoptosis

Cancer Res.

Adriamycin inhibits adipogenesis through the modulation of PPARγ and restoration of adriamycin-mediated inhibition of adipogenesis by PPARγ over-expression

Toxicol. Mech. Methods

Moderate endurance training prevents doxorubicin-induced in vivo mitochondriopathy and reduces the development of cardiac apoptosis

Am. J. Physiol. Heart Circ. Physiol.

The role of nitric oxide in doxorubicin-induced cardiotoxicity: experimental study

Turk. J. Haematol.

Taking diabetes to heart—deregulation of myocardial lipid metabolism in diabetic cardiomyopathy

J. Am. Heart Assoc.

Adriamycin-induced oxidative mitochondrial cardiotoxicity

Cell Biol. Toxicol.

Persistent alterations in the gene expression profile of the heart subsequent to chronic doxorubicin treatment

Cardiovasc. Toxicol. Cardiovasc. Toxicol.

Neuregulin-1 attenuated the doxorubicin-induced decrease in cardiac troponins

Am. J. Physiol. Heart Circ. Physiol.

Anthracycline cardiomyopathy monitored by morphologic changes

Cancer Treat. Rep.

Mitochondrial energetics in the heart in obesity-related diabetes direct evidence for increased uncoupled respiration and activation of uncoupling proteins

Diabetes

Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release

J. Cardiovasc. Pharmacol.

Drug-induced cardiac mitochondrial toxicity and protection: from doxorubicin to carvedilol

Curr. Pharm. Des.