Association of Cardiotoxicity With Doxorubicin and Trastuzumab: A Double-Edged Sword in Chemotherapy

Abstract

Anticancer drugs play an important role in reducing mortality rates and increasing life expectancy in cancer patients. Treatments include monotherapy and/or a combination of radiation therapy, chemotherapy, hormone therapy, or immunotherapy. Despite great advances in drug development, some of these treatments have been shown to induce cardiotoxicity directly affecting heart function and structure, as well as accelerating the development of cardiovascular disease. Such side effects restrict treatment options and can negatively affect disease management. Consequently, when managing cancer patients, it is vital to understand the mechanisms causing cardiotoxicity to better monitor heart function, develop preventative measures against cardiotoxicity, and treat heart failure when it occurs in this patient population. This review discusses the role and mechanism of major chemotherapy agents with principal cardiovascular complications in cancer patients.

Keywords: cancer; cardiotoxicity; chemotherapy; doxorubicin; trastuzumab.

Figure 1. Cardiotoxicity.

According to the Cardiac Review and Evaluation Committee, cardiotoxicity leads to cardiomyopathy, tachycardia, heart failure, and LV dysfunction. LV: left ventricular

Figure 2. Classes of antineoplastic agents used as chemotherapy and representatives of each class.

Anticancer drugs are divided into four groups: (1) cytotoxic (e.g., anthracyclines, antimetabolic, alkylating agents, and derivatives of plants); (2) kinase inhibitors (e.g., analogs, antagonists, and aromatase inhibitors; (3) hormones, (e.g., tyrosine kinase and pan-kinase inhibitors); and (4) monoclonal antibodies (e.g., trastuzumab, anti-EGF, anti-CD20, anti-CD3, and anti-VEGF). EGF: epidermal growth factor; CD: cluster of differentiation; VEGF: vascular endothelial growth factor

Figure 3. Types of cardiotoxicity.

Cardiotoxicity is classified into type 1 and type 2. Type I is irreversible and dose-dependent, whereas type 2 is reversible and dose-independent.

Figure 4. Cardiotoxicity by doxorubicin.

Doxorubicin acts on TOP2B causing breaks in genomic and mitochondrial DNA, and, as a consequence, elevating ROS. Additionally, ferric iron forms a complex with doxorubicin that generates even more free radicals via NADPH oxidase and lipid peroxidation. Furthermore, doxorubicin disrupts autophagy flux in cardiomyocytes by impairing lysosome acidity and function. All these mechanisms impair cardiomyocytes and are cardiotoxic. TOP2B: DNA topoisomerase II beta; ROS: reactive oxygen species. O₂^.: superoxide anion. Fe²⁺: ferric anion. NADPH: nicotinamide adenine dinucleotide phosphate

Figure 5. Cardiotoxicity by trastuzumab.

Trastuzumab acts on HER2, decreasing signaling via the MEK/ERK pathway and causing apoptosis. It also downregulates the antiapoptotic protein BCL-XL and upregulates the proapoptotic protein BCL-XS; impairs the PI3K/mTOR pathway, causing decrease in autophagy and protein synthesis; and decreases the MAPK activity, dampening protein synthesis. Together, these impairments are cardiotoxic HER2: human epidermal growth factor 2; BCL-XL: B-cell lymphoma-extra large; BCL-XS: B-cell lymphoma-extra small; PIP2: phosphorylate phosphatidylinositol 4,5 bisphosphate; PIP3: phosphatidylinositol 3,4,4-triphosphate; MAPK: mitogen-activated protein kinase; mTOR: mammalian target of rapamycin

Figure 6. A comprehensive plan for the cardio-oncologist to address comorbidities when personalizing treatment for a cancer patient.

Patient education and drug screening are key because they allow the cardio-oncologist to detect cardiotoxicity in its earliest stages. Additionally, pathway analysis should point to new techniques for managing cardiovascular disease in cancer patients. Finally, translational investigation and drug monitoring must be incorporated into any cardio-oncology program.