Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase II beta Interaction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F20%3A10418075" target="_blank" >RIV/00216208:11150/20:10418075 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11160/20:10418075

Result on the web

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=1b.1hUNkdG" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=1b.1hUNkdG</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1124/jpet.119.264580" target="_blank" >10.1124/jpet.119.264580</a>

Result language

angličtina

Original language name

Investigation of Structure-Activity Relationships of Dexrazoxane Analogs Reveals Topoisomerase II beta Interaction as a Prerequisite for Effective Protection against Anthracycline Cardiotoxicity

Original language description

Bisdioxopiperazine agent dexrazoxane (ICRF-187) has been the only effective and approved drug for prevention of chronic anthracycline cardiotoxicity. However, the structure-activity relationships (SARs) of its cardioprotective effects remain obscure owing to limited investigation of its derivatives/analogs and uncertainties about its mechanism of action. To fill these knowledge gaps, we tested the hypothesis that dexrazoxane derivatives exert cardioprotection via metal chelation and/or modulation of topoisomerase II beta (Top2B) activity in chronic anthracycline cardiotoxicity. Dexrazoxane was alkylated in positions that should not interfere with the metal-chelating mechanism of cardioprotective action; that is, on dioxopiperazine imides or directly on the dioxopiperazine ring. The protective effects of these agents were assessed in vitro in neonatal cardiomyocytes. All studied modifications of dexrazoxane molecule, including simple methylation, were found to abolish the cardioprotective effects. Because this challenged the prevailing mechanistic concept and previously reported data, the two closest derivatives [(+/-)-4,4&apos;-(propane-1,2-diyl)bis(1-methylpiperazine-2,6-dione) and 4-(2-(3,5-dioxopiperazin-1-yl)ethyl)-3-methylpiperazine-2,6-dione] were thoroughly scrutinized in vivo using a rabbit model of chronic anthracycline cardiotoxicity. contrast to dexrazoxane, both compounds failed to protect the heart, as demonstrated by mortality, cardiac dysfunction, and myocardial damage parameters, although the pharmacokinetics and metal-chelating properties of their metabolites were comparable to those of dexrazoxane. The loss of cardiac protection was shown to correlate with their abated potential to inhibit and deplete Top2B both in vitro and in vivo. These findings suggest a very tight SAR between bisdioxopiperazine derivatives and their cardioprotective effects and support Top2B as a pivotal upstream druggable target for effective cardioprotection against anthracycline cardiotoxicity. SIGNIFICANCE STATEMENT This study has revealed the previously unexpected tight structure-activity relationships of cardioprotective effects in derivatives of dexrazoxane, which is the only drug approved for the prevention of cardiomyopathy and heart failure induced by anthracycline anticancer drugs. The data presented in this study also strongly argue against the importance of metalchelating mechanisms for the induction of this effect and support the viability of topoisomerase II beta as an upstream druggable target for effective and clinically translatable cardioprotection.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30104 - Pharmacology and pharmacy

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Pharmacology and Experimental Therapeutics

ISSN

0022-3565

e-ISSN

—

Volume of the periodical

373

Issue of the periodical within the volume

3

Country of publishing house

US - UNITED STATES

Number of pages

14

Pages from-to

402-415

UT code for WoS article

000551159700008

EID of the result in the Scopus database

2-s2.0-85084869801