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SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization

Oncogene volume 23, pages 873–882 (2004)Cite this article

Abstract

Loss of the DNA-dependent protein kinase (DNA-PK) results in increased sensitivity to ionizing radiation due to inefficient repair of DNA double-strand breaks. Overexpression of DNA-PK in tumor cells conversely results in resistance to ionizing radiation. It is therefore possible that inhibition of DNA-PK will enhance the preferential killing of tumor cells by radiotherapy. Available inhibitors of DNA-PK, like wortmannin, are cytotoxic and stop the cell cycle because they inhibit phoshatidylinositol-3-kinases at 100-fold lower concentrations required to inhibit DNA-PK. In an effort to develop a specific DNA-PK inhibitor, we have characterized SU11752, from a three-substituted indolin-2-ones library. SU11752 and wortmannin were equally potent inhibitors of DNA-PK. In contrast, inhibition of the phoshatidylinositol-3-kinase p110γ required 500-fold higher concentration of SU11752. Thus, SU11752 was a more selective inhibitor of DNA-PK than wortmannin. Inhibition kinetics and a direct assay for ATP binding showed that SU11752 inhibited DNA-PK by competing with ATP. SU11752 inhibited DNA double-strand break repair in cells and gave rise to a five-fold sensitization to ionizing radiation. At concentrations of SU11752 that inhibited DNA repair, cell cycle progression was still normal and ATM kinase activity was not inhibited. We conclude that SU11752 defines a new class of drugs that may serve as a starting point for the development of specific DNA-PK inhibitors.

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Abbreviations

DSB:

DNA double-stranded break

DNA-PK:

DNA-dependent protein kinase

DNA-PKcs:

the catalytic subunit of DNA-PK

ssDNA:

single-stranded DNA

dsDNA:

double-stranded DNA

PI3-kinase:

phosphatidylinositol-3 kinase

ATM:

ataxia telangiectasia mutated

ATR:

ATM and rad3-related

PBS:

phosphate-buffered saline

TBS:

Tris-buffered saline

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Acknowledgements

We thank Matthias Wymann for supplying the anti-wortmannin antibody, and Per Elias and Henrik Zetterberg for careful reading of the manuscript. OH was supported by the Swedish Cancer Society, Swedish research council, King Gustav V Jubilee Clinic Cancer Research Foundation, and Sahlgren's University Hospital Research Foundation.

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  1. Ismail Hassan Ismail and Susanne Mårtensson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Chemistry, Göteborg University, Sahlgrenska University Hospital, Göteborg, 41345, Sweden

    Ismail Hassan Ismail, Susanne Mårtensson & Ola Hammarsten

  2. SUGEN, Inc., 230 East Grand Avenue, South San Francisco, 94080-4811, CA, USA

    Deborah Moshinsky, Audie Rice, Cho Tang, Anthony Howlett & Gerald McMahon

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  1. Ismail Hassan Ismail
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Correspondence to Ola Hammarsten.

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Ismail, I., Mårtensson, S., Moshinsky, D. et al. SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization. Oncogene 23, 873–882 (2004). https://doi.org/10.1038/sj.onc.1207303

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