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Blood, 15 June 2004, Vol. 103, No. 12, pp. 4659-4665.
Prepublished online as a Blood First Edition Paper on March 9, 2004; DOI 10.1182/blood-2003-07-2527.
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NEOPLASIA
A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia
Elaine Willmore,
Sarah de Caux,
Nicola J. Sunter,
Michael J. Tilby,
Graham H. Jackson,
Caroline A. Austin, and
Barbara W. Durkacz
From the School of Cell and Molecular Biosciences, University of Newcastle-upon-Tyne Medical School, Newcastle-upon-Tyne, United Kingdom; Northern Institute for Cancer Research, University of Newcastle-upon-Tyne Medical School, Newcastle-upon-Tyne, United Kingdom; and Department of Hematology, Royal Victoria Infirmary, Newcastle-upon-Tyne, United Kingdom.
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 µM) 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 II or  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. (Blood. 2004;103:4659-4665)
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