期刊
ACS CHEMICAL BIOLOGY
卷 14, 期 6, 页码 1110-1114出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.9b00144
关键词
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资金
- CRUK Programme Grant [C6563/A16771]
- Wellcome Trust Sussex Drug Discovery Award [110578/Z/15/Z]
- Wellcome Trust [110578/Z/15/Z] Funding Source: Wellcome Trust
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.
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