title: Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone.
abstract: Anthracyclines, e.g., doxorubicin (DOX), and anthracenediones, e.g., mitoxantrone (MTX), are drugs used in the chemotherapy of several cancer types, including solid and non-solid malignancies such as breast cancer, leukemia, lymphomas, and sarcomas. Although they are effective in tumor therapy, treatment with these two drugs may lead to side effects such as arrhythmia and heart failure. At the same clinically equivalent dose, MTX causes slightly reduced cardiotoxicity compared with DOX. These drugs interact with iron to generate reactive oxygen species (ROS), target topoisomerase 2 (Top2), and impair mitochondria. These are some of the mechanisms through which these drugs induce late cardiomyopathy. In this review, we compare the cardiotoxicities of these two chemotherapeutic drugs, DOX and MTX. As described here, even though they share similarities in their modes of toxicant action, DOX and MTX seem to differ in a key aspect. DOX is a more redox-interfering drug, while MTX induces energy imbalance. In addition, DOX toxicity can be explained by underlying mechanisms that include targeting of Top2 beta, mitochondrial impairment, and increases in ROS generation. These modes of action have not yet been demonstrated for MTX, and this knowledge gap needs to be filled.
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS, Brazil.|Graduate Program in Cellular and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: Roberto Marques
authors.initials: RM
authors.lastname: Damiani
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS, Brazil.|Department of Pharmacosciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors.forename: Dinara Jaqueline
authors.initials: DJ
authors.lastname: Moura
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS, Brazil.
authors.forename: Cassiana Macagnan
authors.initials: CM
authors.lastname: Viau
authors.affiliation: Department of Pharmacosciences, Federal University of Health Sciences of Porto Alegre (UFCSPA), Porto Alegre, RS, Brazil.
authors.forename: Rafael Andrade
authors.initials: RA
authors.lastname: Caceres
authors.affiliation: Graduate Program in Cellular and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.|Department of Biophysics, Center of Biotechnology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
authors.forename: João Antonio Pêgas
authors.initials: JAP
authors.lastname: Henriques
authors.affiliation: Laboratory of Genetic Toxicology, Federal University of Health Sciences of Porto Alegre (UFCSPA), Rua Sarmento Leite, 245, Porto Alegre, RS, Brazil. jenifers@ufcspa.edu.br.|Graduate Program in Cellular and Molecular Biology, Federal University of Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. jenifers@ufcspa.edu.br.
authors.forename: Jenifer
authors.initials: J
authors.lastname: Saffi
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000951:Antigens, Neoplasm / Q000378:metabolism; D066126:Cardiotoxicity; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007501:Iron / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008942:Mitoxantrone / Q000633:toxicity*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
chemical_list: D000903:Antibiotics, Antineoplastic; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D017382:Reactive Oxygen Species; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D008942:Mitoxantrone; D007501:Iron; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human
keywords: Cardiotoxicity; Doxorubicin; Mitoxantrone; Topoisomerase