Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective

Abstract

Antineoplastic drugs can be associated with several side effects, including cardiovascular toxicity (CTX). Biochemical studies have identified multiple mechanisms of CTX. Chemoterapeutic agents can alter redox homeostasis by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species RNS. Cellular sources of ROS/RNS are cardiomyocytes, endothelial cells, stromal and inflammatory cells in the heart. Mitochondria, peroxisomes and other subcellular components are central hubs that control redox homeostasis. Mitochondria are central targets for antineoplastic drug-induced CTX. Understanding the mechanisms of CTX is fundamental for effective cardioprotection, without compromising the efficacy of anticancer treatments. Type 1 CTX is associated with irreversible cardiac cell injury and is typically caused by anthracyclines and conventional chemotherapeutic agents. Type 2 CTX, associated with reversible myocardial dysfunction, is generally caused by biologicals and targeted drugs. Although oxidative/nitrosative reactions play a central role in CTX caused by different antineoplastic drugs, additional mechanisms involving directly and indirectly cardiomyocytes and inflammatory cells play a role in cardiovascular toxicities. Identification of cardiologic risk factors and an integrated approach using molecular, imaging, and clinical data may allow the selection of patients at risk of developing chemotherapy-related CTX. Although the last decade has witnessed intense research related to the molecular and biochemical mechanisms of CTX of antineoplastic drugs, experimental and clinical studies are urgently needed to balance safety and efficacy of novel cancer therapies.

The novel butyrate derivative phenylalanine‐butyramide protects from doxorubicin‐induced cardiotoxicity

“…One of the main mechanisms of DOXO‐induced cardiotoxicity involves an increase in oxidative and nitrosative stress . Hence, we tested whether the protection conferred by FBA was achieved by re‐establishing the nitroso–redox balance.…”

“…Several strategies have been developed in order to protect the heart from DOXO cardiotoxicity, including limitation of cumulative dose and molecules aimed at lowering oxidative stress. However, the use of these agents is somehow still controversial . Great interest has been paid to the potentiality of prebiotics and probiotics in reducing cardiovascular risk, sustaining the key role of gut microbiota in preventing cardiovascular diseases such as hypertension, metabolic syndrome and hypercholesterolaemia .…”

“…The use of dexrazoxane has been clinically evaluated in doxorubicin‐treated children with acute lymphoblastic leukaemia, resulting in reduced myocardial injury, as indicated by decreased serum troponin T . However, none of these strategies is unanimously recommended, emphasizing the need for further studies …”

Doxorubicin Cardiotoxicity: Multiple Targets and Translational Perspectives

“…Traditionally, the main mechanism accounting for cardiotoxic potential of anthracyclines has been attributed to the excessive production of reactive oxygen and nitrogen species (ROS and RNS) [10]. This overproduction is facilitated by permissive conditions due to low antioxidant capacity, in terms of ROS-scavenging enzyme synthesis, possessed by a cardiomyocyte.…”

“…NOX2 and NOX4 isoforms are predominantly expressed in the heart where they contribute to enhancement in oxidative stress. Growing evidence has demonstrated an increased and persistent activation of these enzymes in response to DOX exposure [10].…”