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

0511335 - ÚMG 2020 RIV US eng J - Journal Article
Komulainen, E. - Pennicott, L. - Le Grand, D. - Caldecott, Keith
Deazaflavin Inhibitors of TDP2 with Cellular Activity Can Affect Etoposide Influx and/or Efflux.
ACS Chemical Biology. Roč. 14, č. 6 (2019), s. 1110-1114. ISSN 1554-8929. E-ISSN 1554-8937
Institutional support: RVO:68378050
Keywords : 5'-tyrosyl dna phosphodiesterase * small-molecule inhibitors * strand break repair * topoisomerase-ii * enzyme
OECD category: Cell biology
Impact factor: 4.434, year: 2019
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acschembio.9b00144

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.
Permanent Link: http://hdl.handle.net/11104/0306729