Autoren:	Deng, Shiwei Yan, Tiandong Jendrny, Cathleen Nemecek, Andrea Vincetic, Mladen Gödtel-Armbrust, Ute Wojnowski, Leszek
Titel:	Dexrazoxane may prevent doxorubicin-induced DNA damage via depleting both topoisomerase II isoforms
Online-Publikationsdatum:	12-Okt-2022
Erscheinungsdatum:	2014
Sprache des Dokuments:	Englisch
Zusammenfassung/Abstract:	BACKGROUND: The bisdioxopiperazine dexrazoxane (DRZ) prevents anthracycline-induced heart failure, but its clinical use is limited by uncertain cardioprotective mechanism and by concerns of interference with cancer response to anthracyclines and of long-term safety. METHODS: We investigated the effects of DRZ on the stability of topoisomerases IIalpha (TOP2A) and IIbeta (TOP2B) and on the DNA damage generated by poisoning these enzymes by the anthracycline doxorubicin (DOX). RESULTS: DRZ given i.p. transiently depleted in mice the predominant cardiac isoform Top2b. The depletion was also seen in H9C2 cardiomyocytes and it was attenuated by mutating the bisdioxopiperazine binding site of TOP2B. Consistently, the accumulation of DOX-induced DNA double strand breaks (DSB) by wild-type, although not by mutant TOP2B, was reduced by DRZ. In contrast, the DRZ analogue ICRF-161, which is capable of iron chelation but not of TOP2B binding and cardiac protection, did not deplete TOP2B and did not prevent the accumulation of DOX-induced DSB. TOP2A, re-expressed in cultured cardiomyocytes by fresh serum, was depleted by DRZ along with TOP2B. DRZ depleted TOP2A also from fibrosarcoma-derived cells, but not from lung cancer-derived and human embryo-derived cells. DRZ-mediated TOP2A depletion reduced the accumulation of DOX-induced DSB. CONCLUSIONS: Taken together, our data support a model of anthracycline-induced heart failure caused by TOP2B-mediated DSB and of its prevention by DRZ via TOP2B degradation rather than via iron chelation. The depletion of TOP2B and TOP2A suggests an explanation for the reported DRZ interference with cancer response to anthracyclines and for DRZ side-effects.
DDC-Sachgruppe:	610 Medizin 610 Medical sciences
Veröffentlichende Institution:	Johannes Gutenberg-Universität Mainz
Organisationseinheit:	FB 04 Medizin
Veröffentlichungsort:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-7952
Version:	Published version
Publikationstyp:	Zeitschriftenaufsatz
Nutzungsrechte:	CC BY
Informationen zu den Nutzungsrechten:	https://creativecommons.org/licenses/by/4.0/
Zeitschrift:	BMC cancer 14
Seitenzahl oder Artikelnummer:	Art. 842
Verlag:	BioMed central
Verlagsort:	London
Erscheinungsdatum:	2014
ISSN:	1471-2407
URL der Originalveröffentlichung:	http://dx.doi.org/10.1186/1471-2407-14-842
DOI der Originalveröffentlichung:	10.1186/1471-2407-14-842
Enthalten in den Sammlungen:	DFG-OA-Publizieren (2012 - 2017)