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Influence of PARP-1 Inhibition in the Cardiotoxicity of the Topoisomerase 2 Inhibitors Doxorubicin and Mitoxantrone

Influence of PARP-1 Inhibition in the Cardiotoxicity of the Topoisomerase 2 Inhibitors Doxorubicin and Mitoxantrone

Roberto Marques Damiani, Dinara Jaqueline Moura, Cassiana Macagnan Viau, Verônica Brito, Ana Moira Morás, João Antonio Pêgas Henriques, Jenifer Saffi

Toxicol In Vitro. 2018 Oct;52:203-213.

PMID: 29913208

Abstract:

Doxorubicin (DOX) and Mitoxantrone (MTX) are very effective drugs for a range of tumors despite being highly cardiotoxic. DNA topoisomerase 2 beta (Top2ß) was revealed as key mediator of DOX-induced cardiotoxicity, although ROS generation is also an important mechanism. Oxidative stress is also an important issue in MTX-induced cardiotoxicity that is manifested by mitochondrial dysfunction. Studies have demonstrated the relationship between PARP-1 overactivation and cell viability in DOX-treated cardiomyocytes. In reference of MTX, data regarding PARP-1 overactivation as the mechanism responsible for cardiotoxicity is difficult to find. The aim of this study was to evaluate the influence of PARP-1 inhibitor DPQ on DOX- and MTX-mediated cardiotoxicity. Cells were exposed for 24 h to DOX or MTX in the presence or absence of DPQ. Viability, apoptosis, and genotoxicity assays were carried out. Immunofluorescence of phosphorylated histone H2AX was analyzed in H9c2 cells and cardiomyocytes from neonatal rats. Results demonstrated that DPQ co-treatment increases DOX-induced apoptosis in H9c2 cells. DPQ also prevents DOX and MTX-ROS generation in part by increasing SOD and CAT activities. Furthermore, DPQ co-treatment increased the generation of DNA strand breaks by DOX and MTX whilst also inducing phosphorylation of H2AX, MRE11, and ATM in H9c2 cells. Our results demonstrated that as well as increasing DNA damage and inducing apoptotic cell death, DPQ enhances DOX- and MTX-mediated cytotoxicity in H9c2.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP129075736-A	DPQ		129075-73-6	Price

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