Adriamycin-induced oxidative mitochondrial cardiotoxicity

Abstract

The anticancer agent Adriamycin (ADR) has long been recognized to induce a dose-limiting cardiotoxicity. Numerous studies have attempted to characterize and elucidate the mechanism(s) behind its cardiotoxic effect. Despite a wealth of data covering a wide-range of effects mediated by the drug, the definitive mechanism remains a matter of debate. However, there is consensus that this toxicity is related to the induction of reactive oxygen species (ROS). Induction of ROS in the heart by ADR occurs via redox cycling of the drug at complex I of the electron transport chain. Many studies support the theory that mitochondria are a primary target of ADR-induced oxidative stress, both acutely and long-term. This review focuses on the effects of ADR redox cycling on the mitochondrion, which support the hypothesis that these organelles are indeed a major factor in ADR cardiotoxicity. This review has been constructed with particular emphasis on studies utilizing cardiac models with clinically relevant doses or concentrations of ADR in the hope of advancing our understanding of the mechanisms of ADR toxicity. This compilation of current data may reveal valuable insights for the development of therapeutic strategies better tailored to minimizing the dose-limiting effect of ADR.

Morphological alterations induced by doxorubicin on H9c2 myoblasts: nuclear, mitochondrial, and cytoskeletal targets

“…Scale bar corresponds to 10 μm vitro studies using primary cardiomyocytes (Gabrielson et al 2007;Solem et al 1996;Zhou et al 2001) or other cell lines (L'Ecuyer et al 2001;Spallarossa et al 2004) have been widely reported in the literature. From the different models used, some conclusions are common to all: (a) Dox is activated at the mitochondrial level, forming a semiquinone radical, and (b) Dox causes oxidative stress in cardiac cells that particularly affects mitochondria (Berthiaume and Wallace 2007;Wallace 2003).…”

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

“…The mechanism of DOX's cardiotoxicity is complex and may involve oxidative (2,3), nitrosative and nitrative stress (4,5), mitochondrial dysfunction/ toxicity (1,(6)(7)(8), dysregulation of various metabolic (9) and lipid signaling pathways (10)(11)(12), activation of various stress kinases and cell death mechanisms (both apoptotic and necrotic) (13), triggering of secondary inflammation and remodeling (14), eventually culminating in cardiac dysfunction and heart failure (1,15).…”

Doxorubicin increases the susceptibility of brain mitochondria to Ca2+-induced permeability transition and oxidative damage

“…However, the chronic administration of this drug can induce toxicity to nontarget tissues, cardiotoxicity being the best known side effect [2]. DOX-induced cardiotoxicity has been attributed to a number of effects, including the direct inhibition of key transporters involved in ion homeostasis, alterations in cellular iron and calcium metabolism, disruption of sarcoplasmic reticulum function, mitochondrial dysfunction, and apoptotic cell loss [3]. The mechanisms underlying these events seem to be linked to an increased production of reactive oxygen species (ROS) and oxidative damage [3].…”

“…DOX-induced cardiotoxicity has been attributed to a number of effects, including the direct inhibition of key transporters involved in ion homeostasis, alterations in cellular iron and calcium metabolism, disruption of sarcoplasmic reticulum function, mitochondrial dysfunction, and apoptotic cell loss [3]. The mechanisms underlying these events seem to be linked to an increased production of reactive oxygen species (ROS) and oxidative damage [3]. Oxidative stress results from an imbalance between the generation of ROS and reactive nitrogen species and their removal by the cellular antioxidant system [4] and has been implicated in many neurodegenerative disorders [5,6].…”