Exploring the effects of topoisomerase II inhibitor XK469 on anthracycline cardiotoxicity and DNA damage
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F24%3A10488273" target="_blank" >RIV/00216208:11150/24:10488273 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11160/24:10488273
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=PK4WIsABhz" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=PK4WIsABhz</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1093/toxsci/kfae008" target="_blank" >10.1093/toxsci/kfae008</a>
Alternative languages
Result language
angličtina
Original language name
Exploring the effects of topoisomerase II inhibitor XK469 on anthracycline cardiotoxicity and DNA damage
Original language description
Anthracyclines, such as doxorubicin (adriamycin), daunorubicin, or epirubicin, rank among the most effective agents in classical anticancer chemotherapy. However, cardiotoxicity remains the main limitation of their clinical use. Topoisomerase II beta has recently been identified as a plausible target of anthracyclines in cardiomyocytes. We examined the putative topoisomerase II beta selective agent XK469 as a potential cardioprotective and designed several new analogs. In our experiments, XK469 inhibited both topoisomerase isoforms (alpha and beta) and did not induce topoisomerase II covalent complexes in isolated cardiomyocytes and HL-60, but induced proteasomal degradation of topoisomerase II in these cell types. The cardioprotective potential of XK469 was studied on rat neonatal cardiomyocytes, where dexrazoxane (ICRF-187), the only clinically approved cardioprotective, was effective. Initially, XK469 prevented daunorubicin-induced toxicity and p53 phosphorylation in cardiomyocytes. However, it only partially prevented the phosphorylation of H2AX and did not affect DNA damage measured by Comet Assay. It also did not compromise the daunorubicin antiproliferative effect in HL-60 leukemic cells. When administered to rabbits to evaluate its cardioprotective potential in vivo, XK469 failed to prevent the daunorubicin-induced cardiac toxicity in either acute or chronic settings. In the following in vitro analysis, we found that prolonged and continuous exposure of rat neonatal cardiomyocytes to XK469 led to significant toxicity. In conclusion, this study provides important evidence on the effects of XK469 and its combination with daunorubicin in clinically relevant doses in cardiomyocytes. Despite its promising characteristics, long-term treatments and in vivo experiments have not confirmed its cardioprotective potential.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - 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
Result continuities
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)
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Toxicological Sciences
ISSN
1096-6080
e-ISSN
1096-0929
Volume of the periodical
198
Issue of the periodical within the volume
2
Country of publishing house
US - UNITED STATES
Number of pages
15
Pages from-to
288-302
UT code for WoS article
001157824100001
EID of the result in the Scopus database
2-s2.0-85189438986