From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview

Abstract

Significance: Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Recent Advances: Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. Critical Issues: CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Future Directions: Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system.

Keywords: ErbB2 inhibitors; cancer immunotherapy; chemotherapy; oxidative/nitrosative stress; tyrosine kinase inhibitors; vascular endothelial growth factor.

FIG. 1.

Concentric representation of cardiotoxic effects of anthracyclines. ROS, reactive oxygen species.

FIG. 2.

Simplified algorithm showing the factors related to anthracycline therapy or patient characteristics that may determine cardiac damage.

FIG. 3.

ErbB receptor homodimerization or heterodimerization is induced by stressors, including anthracycline therapy, with consequent complex intracellular pathway activation. Cascade effects can be avoided by treatment with monoclonal antibodies and TKIs. See the text for further explanation. EGFR, epidermal growth factor receptor; ErbB2 (or HER2), human epidermal growth factor receptor 2; ERK, extracellular signal-regulated kinase; TKIs, tyrosine kinase inhibitors.

FIG. 4.

VEGFR activation triggers a complex intracellular pathway. Cascade effects can be avoided by treatment with anti-angiogenic drugs acting at various levels of the cascade. See the text for further explanation. MAPK, mitogen-activated protein kinase; NO, nitric oxide; NOS, nitric oxide synthase; VEGFR, vascular endothelial growth factor receptor.

FIG. 5.

Schematic illustration of how TKI antagonists induce cardiac damage; these drugs can increase arterial pressure and ventricular-vascular coupling, leading to heart failure. PDGFR, platelet-derived growth factor receptor; VEGF, vascular endothelial growth factor.

FIG. 6.

Role of CTLA-4 and its interaction with ipilimumab in tumor immunity. (A) Dying tumor cells release tumor neo-antigens that are taken up by APCs, which then present B7 co-stimulatory molecules to T cells. T cells recognize tumor neo-antigens on APCs and are activated. Activated T cells upregulate inhibitory checkpoints, such as CTLA-4 and PD-1, which block T cell activation and attack of tumor cells. (B) Ipilimumab blocks CTLA-4, resulting in T cell activation and destruction of tumor cells. See the text for further explanation and acronyms. APCs, antigen-presenting cells; CTLA-4, cytotoxic T lymphocyte-associated protein 4; PD-1, programmed cell death 1; TCR, T cell receptor.

FIG. 7.

Main cardiotoxic mechanism and effects induced by antimetabolite drugs. See the text for further explanation. 5-FU, 5-fluorouracil; HF, heart failure; RNS, reactive nitrogen species; ROS, reactive oxygen species.

FIG. 8.

Physiological function of the redox system. See the text for further explanation. GPx, glutathione peroxidase; H₂O₂, hydrogen peroxide; NOSs, nitric oxide synthases; ONOO⁻, peroxynitrite; SNO, S-nitrosylation; SOD, superoxide dismutase.

FIG. 9.

In the case of excessive production of superoxide anion (O₂^•−) and other ROS/RNS, lipid and protein oxidation/nitration may occur, with consequent alteration of the activity of many enzymes, leading to cell death. The dashed arrow represents the onset of a vicious cycle affecting redox enzymes. See the text for further explanation. NOX, NAD(P)H oxidase.

FIG. 10.

Antioxidant properties of NO. When production of NO is adequate, the formation of nitrosylating agents may prevail, including N₂O₃, which can mediate a direct thiol nitrosylation of proteins, which, in turn, may affect the regulatory function in many physiological processes. See the text for further explanation.

FIG. 11.

Drugs and cardioprotective strategies against antineoplastic-induced cardiotoxicity. The main mechanism(s) of protection are reported. See the text for further explanation. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; NRG1, neuregulin 1; Top2, topoisomerase 2.

FIG. 12.

Simplified algorithm showing how cancer therapy alone or together with demographic and conventional risk factors may determine cardiac damage; both factors can increase myocardial and arterial stiffness, thus impairing ventricular-vascular coupling and, finally, leading to HF, with either decreased ejection fraction (EF) or preserved EF (HFPEF). CV, cardiovascular.