Role of mtDNA lesions in anthracycline cardiotoxicity

Abstract

Doxorubicin (adriamycin) is an effective drug in the treatment of many malignancies. Its prolonged use is, however, limited by an irreversible, dose-dependent and progressive cardiomyopathy, which may become evident even years after completion of therapy. Data from rats and humans show that oxidative phosphorylation is impaired rapidly after acute doxorubicin-exposure. Such respiratory chain dysfunction is known to enhance the production of reactive oxygen species and may lead to quantitative and qualitative injury of mitochondrial DNA (mtDNA) and its encoded respiratory chain subunits. MtDNA depletion, mtDNA mutations and respiratory defects then accumulate with time also in the absence of continued anthracycline exposure. Chronic cardiotoxicity then manifests, when the bioenergetic capacity of the organelles is severely impaired. The mitochondrial damage in late-onset doxorubicin cardiomyopathy is heart specific and not found in skeletal muscle. DOXO-EMCH, a 6-maleimidocaproyl hydrazone derivative of doxorubicin has evolved from the search for less cardiotoxic anthracyclines. At equieffective antitumor doses, DOXO-EMCH has a substantially lower heart toxicity than free doxorubicin.

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

“…85,86 Abnormal respiratory chain function may enhance the formation of ROS and thereby further injure the respiratory chain or mitochondrial DNA and its encoded respiratory chain subunits. 87 The sum of these actions is to alter mitochondrial function and ultimately cause myocyte death.…”

Functional Cardiotoxicity Profiling and Screening Using the xCELLigence RTCA Cardio System

“…1,5 In addition to testing for hERG, lead compounds and drug candidates are also subjected to assays, which screen for direct damage to cardiomyocytes at the cellular or organellar level, such as mitochondria. 3,7 Anthracyclines, a widely used class of chemotherapeutic drugs, is known to induce heart damage by direct toxicity and their use is often hampered by their cumulative doselimiting cardiotoxicity. 3,7,8 It is imperative to emphasize that while studying the effect of drug candidates on individual ion channels and cellular events may provide useful information, what is really needed is a functional assay system that can assess the integrated cardiac response to drug candidates.…”

“…3,7 Anthracyclines, a widely used class of chemotherapeutic drugs, is known to induce heart damage by direct toxicity and their use is often hampered by their cumulative doselimiting cardiotoxicity. 3,7,8 It is imperative to emphasize that while studying the effect of drug candidates on individual ion channels and cellular events may provide useful information, what is really needed is a functional assay system that can assess the integrated cardiac response to drug candidates. Currently, these types of studies are mainly performed in whole organ perfusion assays referred to as Langendorff heart assay or telemetry experiments using live animals.…”

Anthracycline Treatment and Ventricular Remodeling in Left Ventricular Assist Device Patients

“…Intramyocardial formation of secondary alcohol metabolites might play a key role in promoting the development of end-stage HF. [21][22][23] Additional pathogenetic mechanisms currently under investigation include apoptosis, iron metabolism interference, and calcium dysregulation. 24,25 Pathology.…”