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Sensitization of breast carcinoma cells to ionizing radiation by small molecule inhibitors of DNA-dependent protein kinase and ataxia telangiectsia mutated

Lookup NU author(s): Dr Ian Cowell, Emeritus Professor Barbara Durkacz, Dr Michael Tilby

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Abstract

DNA-PK and ATM are members of the phosphatidylinositol 3′-kinase like kinase (PIKK) family of serine/threonine protein kinases and have critical roles in the cellular response to DNA double-strand breaks. Genetic loss of either activity leads to pronounced sensitivity to ionizing radiation (IR). Hence, these enzymes are potential targets to confer enhanced radiosensitivity on tumour cells. We show that novel inhibitors of either DNA-PK or ATM sensitize breast carcinoma cells to IR. Radiosensitization was accompanied by an apparent DNA repair deficit as measured by the persistence of IR-induced foci of phosphorylated histone H2AX (γH2AX foci). These specific inhibitors also allowed us to probe the biochemistry and kinetics of histone H2AX phosphorylation following γ-irradiation in breast cancer cells with the aim of validating H2AX as a biomarker for DNA-PK or ATM inhibition in vivo. ATM inhibition reduced the initial average intensity of γH2AX foci while inhibition of DNA-PK had only a small effect on the initial phosphorylation of H2AX. However, simultaneous treatment with both compounds dramatically reduced γH2AX focus intensity, consistent with the reported role of ATM and DNA-PK in IR induced phosphorylation of H2AX. © 2005 Elsevier Inc. All rights reserved.


Publication metadata

Author(s): Cowell, I.G., Durkacz, B.W., Tilby, M.J.

Publication type: Article

Publication status: Published

Journal: Biochemical Pharmacology

Year: 2005

Volume: 71

Issue: 1-2

Pages: 13-20

Print publication date: 19/12/2005

ISSN (print): 0006-2952

ISSN (electronic): 1873-2968

URL: http://dx.doi.org/10.1016/j.bcp.2005.09.029

DOI: 10.1016/j.bcp.2005.09.029

PubMed id: 16293233


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