A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia.
We report for the first time the use of a selective small-molecule inhibitor of DNA repair to potentiate topoisomerase II (topo II) poisons, identifying DNA-dependent protein kinase (DNA-PK) as a potential target for leukemia therapy. Topo II poisons form cleavable complexes that are processed to DNA double-strand breaks (DSBs). DNA-PK mediates nonhomologous end joining (NHEJ). Inhibition of this DSB repair pathway may sensitize cells to topo II poisons. We investigated the effects of a novel DNA-PK inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), on the response to topo II poisons using K562 leukemia cells. NU7026 (10 microM) potentiated the growth inhibition of idarubicin, daunorubicin, doxorubicin, etoposide, amsacrine (mAMSA), and mitroxantrone with potentiation factors at 50% growth inhibition ranging from approximately 19 for mAMSA to approximately 2 for idarubicin (potentiation of etoposide was confirmed by clonogenic assay). In contrast, NU7026 did not potentiate camptothecin or cytosine arabinoside (araC). NU7026 did not affect the levels of etoposide-induced topo IIalpha or beta cleavable complexes. NU7026 alone had no effect on cell cycle distribution, but etoposide-induced accumulation in G2/M was increased by NU7026. A concentration-dependent increase in etoposide-induced DSB levels was increased by NU7026. The mechanism of NU7026 potentiation of topo II poisons involves inhibition of NHEJ and a G2/M checkpoint arrest.
Willmore
Elaine
E
School of Cell and Molecular Biosciences, University of Newcastle-upon-Tyne Medical School, Newcastle-upon-Tyne NE2 4HH, United Kingdom.
de Caux
Sarah
S
Sunter
Nicola J
NJ
Tilby
Michael J
MJ
Jackson
Graham H
GH
Austin
Caroline A
CA
Durkacz
Barbara W
BW
D000970:Antineoplastic Agents / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D006801:Humans; D020014:K562 Cells; D009025:Morpholines / Q000494:pharmacology*; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D000970:Antineoplastic Agents; D002867:Chromones; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009025:Morpholines; D009687:Nuclear Proteins; D011838:Radiation-Sensitizing Agents; D059005:Topoisomerase II Inhibitors; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases