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Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone

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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.

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Abbreviations

APE:

Apurinic/apyrimidinic endonuclease

BER:

Base excision repair

CAT:

Catalase

DFO:

Deferoxamine

DOX:

Doxorubicin

DSB:

Double-strand break

eNOS:

Endothelial nitric oxide synthase

ETC:

Electron transport chain

HNE:

4-Hydroxy-2-nonenal

HR:

Homologous recombination

MS:

Multiple sclerosis

mtDNA:

Mitochondrial DNA

mtTop:

Mitochondrial topoisomerase

MTX:

Mitoxantrone

MTX-MET:

l-Methionine-conjugated MTX

PAR:

Poly(ADP-ribose)

PARP:

Poly(ADP-ribose) polymerase

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SHR:

Spontaneously hypertensive rats

SNP:

Single nucleotide polymorphism

SOD:

Superoxide dismutase

Top:

Topoisomerase

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Acknowledgments

The authors would like to thank the CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brasília, Brazil—Grant No. 479564/2013-2) and PRONEX–FAPERGS/CNPq (Grant No. 10/0044-3) for grant support.

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Correspondence to Jenifer Saffi.

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The authors declare that there are no conflicts of interest.

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Damiani, R.M., Moura, D.J., Viau, C.M. et al. Pathways of cardiac toxicity: comparison between chemotherapeutic drugs doxorubicin and mitoxantrone. Arch Toxicol 90, 2063–2076 (2016). https://doi.org/10.1007/s00204-016-1759-y

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  • DOI: https://doi.org/10.1007/s00204-016-1759-y

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