Molecular mechanism of doxorubicin-induced cardiomyopathy – An update
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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Equal contribution for the corresponding author.