Teaching the basics of the mechanism of doxorubicin-induced cardiotoxicity: Have we been barking up the wrong tree?

Abstract

Doxorubicin (DOX), or Adriamycin, an anthracycline antibiotic discovered serendipitously as a chemotherapeutic drug several decades ago, is still one of the most effective drugs for treating various adult and pediatric cancers (breast cancer, Hodgkin's disease, lymphoblastic leukemia). However, one of the major side effects of the continuous use of DOX is dose-dependent, long-term, and potentially lethal cardiovascular toxicity (congestive heart failure and cardiomyopathy) in cancer survivors many years after cessation of chemotherapy. In addition, predisposition to cardiotoxicity varied considerably among individuals. The long-held notion that DOX cardiotoxicity is caused by reactive oxygen species formed from the redox-cycling of DOX semiquinone lacks rigorous proof in a chronic animal model, and administration of reactive oxygen species detoxifying agents failed to reverse DOX-induced cardiac problems. In this review, I discuss the pros and cons of the reactive oxygen species pathway as a primary or secondary mechanism of DOX cardiotoxicity, the role of topoisomerases, and the potential use of mitochondrial-biogenesis-enhancing compounds in reversing DOX-induced cardiomyopathy. New approaches for well-designed clinical trials that repurpose FDA-approved drugs and naturally occurring polyphenolic compounds prophylactically to prevent or mitigate cardiovascular complications in both pediatric and adult cancer survivors are needed. Essentially, the focus should be on enhancing mitochondrial biogenesis to prevent or mitigate DOX-induced cardiotoxicity.

Shengxian decoction decreases doxorubicin‑induced cardiac apoptosis by regulating the TREM1/NF‑κB signaling pathway

“…Doxorubicin (DOX) is one of the most effective and widely-accepted anticancer drugs available in clinic ( 1 , 2 ). Unfortunately, its cardiotoxic effects limit its use ( 3 , 4 ), affect the quality of life of patients and may even lead to mortality. Once the cumulative dose of DOX reaches a certain level, the risk of congestive heart failure, dilated cardiomyopathy and even mortality significantly increases ( 5 , 6 ).…”

Functional Redox Proteomics Reveal That Salvia miltiorrhiza Aqueous Extract Alleviates Adriamycin-Induced Cardiomyopathy via Inhibiting ROS-Dependent Apoptosis

“…The anthracycline antibiotic adriamycin (ADR), also known as doxorubicin, is the commonly used chemotherapeutic agent for the treatment of various cancers. However, the severe cardiotoxicity of ADR greatly restricts its clinical utilization [ 1 , 2 ]. Although ADR-related injury appears to be multifactorial and complicated, oxidative stress and mitochondrial dysfunction have been proposed to majorly account for the pathogenesis of ADR-induced cardiomyopathy [ 3 – 6 ].…”

Shenmai Injection Protects Against Doxorubicin-Induced Cardiotoxicity via Maintaining Mitochondrial Homeostasis

“…Myocardial injury caused by DOX includes both acute and chronic injuries. Chronic cardiotoxicity of DOX is more common than acute one in clinic (Kalyanaraman, 2020). It manifests progressive myocardial dysfunction after DOX administration and presents development of left ventricular systolic dysfunction (Menna et al, 2008).…”