The serine/threonine protein kinase ATM signals can regulate cell cycle and DNA repair components through phosphorylation on the targets such as p53, CHK2, NBS1, and BRCA1, thus playing a central role in the maintenance of genome integrity. KU-55933 is a specific ATM inhibitor with IC50 value of 13nM and Ki value of 2.2nM (measured by ATM kinase activity). After exposure to 5 Gy of irradiation, treatment with 10μM KU-55933 caused increased phosphorylation of p53 at serine 15 site, a marker of ATM activity, in a time-dependent manner in U2OS cells in within 4 hours.
A range of ATM target phosphorylation events, including pH2AX-ser139, pNBS1-ser343, pCHK1-ser345, or pSMC1-ser966, were decreased by pretreatment with 10μM KU-55933 for 1h before irradiation 3Gy or 15Gy in U2OS cells. The radiosensitization by KU-55933 can be observed in HeLa cells pre-treated with 10μM KU-55933 before a range of ionizing radiation (0-4Gy). Also it can sensitize HeLa cells to the cytotoxic effects of the topoisomerase II inhibitors etoposide, doxorubicin, amsacrine and the topoisomerase I inhibitor camptothecin. These suggested that KU-55933 performed as a radio- and chemosensitizer[1].
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