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Review
. 2018 Mar 7:9:167.
doi: 10.3389/fphys.2018.00167. eCollection 2018.

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective

Gilda Varricchi  1   2 , Pietro Ameri  3 , Christian Cadeddu  4 , Alessandra Ghigo  5 , Rosalinda Madonna  6   7 , Giancarlo Marone  8   9 , Valentina Mercurio  1 , Ines Monte  10 , Giuseppina Novo  11 , Paolo Parrella  1 , Flora Pirozzi  1 , Antonio Pecoraro  1 , Paolo Spallarossa  3 , Concetta Zito  12 , Giuseppe Mercuro  4 , Pasquale Pagliaro  13 , Carlo G Tocchetti  1
Affiliations
Review

Antineoplastic Drug-Induced Cardiotoxicity: A Redox Perspective

Gilda Varricchi et al. Front Physiol. .

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.

Keywords: HER-2 inhibitors; chemotherapy; oxidative/nitrosative stress; tyrosine kinase inhibitors; vascular endothelial growth factor.

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Figures

Figure 1
Figure 1
Schematic representation of some of the cardiovascular toxicities associated with antineoplastic drugs in patients with cancer. Modified with permission from Albini et al. (2010).
Figure 2
Figure 2
Schematic representation of the homeostatic role of ROS and their pathologic role in tumor growth and cell death. Low production of ROS and balanced antioxidant activity play a fundamental role in cellular signaling and repair resulting in controlled growth and survival. Proliferation of tumor cells yields elevated ROS concentrations enhancing cell survival and proliferation leading to DNA damage and genetic instability causing cell dysfunction. Chemotherapeutic agents and radiotherapy increase ROS production to toxic concentrations resulting in irreparable damage to the cell, inadequate adaptations and eventually cell death. The heart is particularly vulnerable to ROS/RNS injury because antioxidant resources are lower than other tissues. Modified with permission from Moloney and Cotter (2017).
Figure 3
Figure 3
Schematic representation of the main mechanisms of anthracycline-induced injury to cardiac cells. The classic model of anthracycline (ANT) cardiotoxicity involves the generation of ROS by the quinone moiety common to all anthracyclines. ROS and RNS hyperproduction results in damage to DNA, protein carbonylation and lipid peroxidation leading to cellular dysfunction and cardiomyocyte death. ANTs can also bind and block the functions of both topoisomerases 2A (TOP2A) and 2B (TOP2B). Tumor cells express high levels of TOP2A, whereas TOP2B is ubiquitously expressed. Cardiomyocytes express TOP2B, but not TOP2A. ANTs form a complex with TOP2B inhibiting its enzymatic activity. Without functional TOP2B, DNA breaks accrue, leading to the activation of p53 tumor-suppressor protein, mitochondrial dysfunction, and the generation of ROS that result in cardiomyocyte death. Another mechanism underlying doxorubicin-dependent oxidative stress is linked to the ability of the drug to directly interfere with the activity of NADPH oxidase and nitric oxide synthase (NOS). Both NADPH oxidase and NOS can transfer electron from NADPH to doxorubicin, causing the formation of semiquinone doxorubicin (SQ-DOX). SQ-DOX in turn transfers electron to O2 and generates O2-. In the NOS compartment, O2- can react with NO to form peroxynitrite (ONOO−), a powerful oxidant that can generate free radicals. An alternative mechanism by which ANTs exert their cardiotoxic effects is the inhibition of neuregulin-1 (NRG-1)-HER-2 in cardiomyocytes. Doxorubicin also induces necrosis of immune (i.e., macrophages) and cancer cells releasing HMGB1 which activates TLR-2 and TLR-4 in cardiomyocytes and inflammatory cells inducing the release of proinflammatory cytokines. These primary effects induce a plethora of secondary effects in cardiomyocytes (e.g., DNA damage, lipid peroxidation, mitochondrial dysfunction, etc.,) which result in cell dysfunction and death. Modified with permission from Tocchetti et al. (2017).
Figure 4
Figure 4
Schematic representation of the mechanism of action of trastuzumab and pathogenesis of its cardiotoxicity. Trastuzumab is a mAb that binds the extracellular domain IV of HER-2. It is used to treat breast cancer patients (≅30%) in which HER-2 is overexpressed and spontaneously homodimerizes or forms heterodimers with other HER receptors, especially HER-3. This ligand-independent activation of HER-2 promotes proliferation and survival of tumor cells. Trastuzumab blocks the interaction HER-2/HER-3 and downstream signaling halting the growth of tumor cells. Moreover, trastuzumab induces the antibody-dependent immune cell-mediated cytotoxicity of cancer cells (left side). In the heart, neuregulin-1 (NRG-1) triggers HER-4/HER-4 homodimerization and HER-4/HER-2 heterodimerization on cardiomyocytes to induce protective pathways in response to stress. Blockade of cardiac HER-2 by trastuzumab results in the disruption of NRG-1-dependent signaling and consequently in alterations of structure and functions that cause cardiomyocyte death (right side).
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