Deazaflavin Inhibitors of TDP2 with Cellular Activity Can Affect Etoposide Influx and/or Efflux

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F19%3A00511335" target="_blank" >RIV/68378050:_____/19:00511335 - isvavai.cz</a>

Result on the web

<a href="https://pubs.acs.org/doi/10.1021/acschembio.9b00144" target="_blank" >https://pubs.acs.org/doi/10.1021/acschembio.9b00144</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acschembio.9b00144" target="_blank" >10.1021/acschembio.9b00144</a>

Result language

angličtina

Original language name

Deazaflavin Inhibitors of TDP2 with Cellular Activity Can Affect Etoposide Influx and/or Efflux

Original language description

Tyrosyl DNA phosphodiesterase 2 (TDP2) facilitates the repair of topoisomerase II (TOP2)-linked DNA double-strand breaks and, as a consequence, is required for cellular resistance to TOP2 ´poisons´. Recently, a deazaflavin series of compounds were identified as potent inhibitors of TDP2, in vitro. Here, however, we show that while some deazaflavins can induce cellular sensitivity to the TOP2 poison etoposide, they do so independently of TDP2 status. Consistent with this, both the cellular level of etoposide-induced TOP2 cleavage complexes and the intracellular concentration of etoposide was increased by incubation with deazaflavin, suggesting an impact of these compounds on etoposide uptake/efflux. In addition, deazaflavin failed to increase the level of TOP2 cleavage complexes or sensitivity induced by m-AMSA, which is a different class of TOP2 poison to which TDP2-defective cells are also sensitive. In conclusion, while deazaflavins are potent inhibitors of TDP2 in vitro, their limited cell permeability and likely interference with etoposide influx/efflux limits their utility in cells.

Czech name

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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

10601 - Cell biology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2019

Confidentiality

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

Name of the periodical

ACS Chemical Biology

ISSN

1554-8929

e-ISSN

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Volume of the periodical

14

Issue of the periodical within the volume

6

Country of publishing house

US - UNITED STATES

Number of pages

5

Pages from-to

1110-1114

UT code for WoS article

000473115900006

EID of the result in the Scopus database

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