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].
KU-55933 showed neuroprotective effects against MPP?-induced neuronal apoptosis, reducing nuclear condensation and DNA fragmentation.
Cell Mol Life Sci. 2010 Nov;67(22):3865-82.
Human corneal epithelial cells (hTCEpi)
10 µM
24 h
Inhibition of ATM activity significantly reduced HSV-1 viral replication and cytopathic effect
Invest Ophthalmol Vis Sci. 2014 Feb 3;55(2):706-15.
KU-55933 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Nude mice
A549 cell xenograft model
Intraperitoneal injection
10 mg/kg
Administered 1 day before radiotherapy and every other day thereafter
To verify the regulatory role of ATM on tumor growth under low-dose radiation. Results showed that the ATM inhibitor alone inhibited the growth of A549 tumors, and the effect was more pronounced when combined with low-dose radiotherapy.
Front Cell Dev Biol. 2021 May 12;9:650819
Apolipoprotein E-deficient mice
High-fat diet-induced atherosclerosis model
Tail vein injection
8 mg/kg
Twice a week for 12 weeks
KU-55933 inhibited atherosclerotic lesion formation and reduced endothelial cell proliferation and inflammation
Proc Natl Acad Sci U S A. 2024 Jan 30;121(5):e2318718121.
Mice
ADR-induced FSGS model
Intraperitoneal injection
500 µg/kg
Every 3 days until sacrifice
Inhibit ATM kinase activity, reduce MAD2B upregulation, and alleviate ADR-induced podocyte injury and proteinuria
Int J Biol Sci. 2021 Oct 22;17(15):4396-4408.
C57BL/6J Mice
HSV-1 keratitis model
Topical eye drops
200 µM
Every 4 hours for 1 day, then every 8 hours for the remainder of the experiment
KU-55933 significantly reduced the severity of stromal keratitis in mice
Invest Ophthalmol Vis Sci. 2014 Feb 3;55(2):706-15.
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