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Inhibition of ATR kinase with the selective inhibitor VE-821 results in radiosensitization of cells of promyelocytic leukaemia (HL-60)

Radiation and environmental biophysics. 2013 Nov ; 52 (4) : 471-9. [epub] 20130811

Radiat Environ Biophys
ISSN 1432-2099 | 0301-634X
Source

Language English Country Germany Media print-electronic

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid23934411

PubMed 23934411
DOI 10.1007/s00411-013-0486-5
Knihovny.cz E-resources

MeSH
Leukemia, Promyelocytic, Acute pathology MeSH
Apoptosis drug effects MeSH
Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors MeSH
HL-60 Cells MeSH
Protein Kinase Inhibitors pharmacology MeSH
G2 Phase Cell Cycle Checkpoints drug effects MeSH
Humans MeSH
Morpholines pharmacology MeSH
DNA Repair drug effects MeSH
Pyrazines pharmacology MeSH
Pyrones pharmacology MeSH
Sulfones pharmacology MeSH
Radiation Tolerance drug effects MeSH
Check Tag
Humans MeSH
Publication type
Journal Article MeSH
Research Support, Non-U.S. Gov't MeSH
Names of Substances
2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one MeSH Browser
3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide MeSH Browser
Ataxia Telangiectasia Mutated Proteins MeSH
ATR protein, human MeSH Browser
Protein Kinase Inhibitors MeSH
Morpholines MeSH
Pyrazines MeSH
Pyrones MeSH
Sulfones MeSH

We compared the effects of inhibitors of kinases ATM (KU55933) and ATR (VE-821) (incubated for 30 min before irradiation) on the radiosensitization of human promyelocyte leukaemia cells (HL-60), lacking functional protein p53. VE-821 reduces phosphorylation of check-point kinase 1 at serine 345, and KU55933 reduces phosphorylation of check-point kinase 2 on threonine 68 as assayed 4 h after irradiation by the dose of 6 Gy. Within 24 h after gamma-irradiation with a dose of 3 Gy, the cells accumulated in the G2 phase (67 %) and the number of cells in S phase decreased. KU55933 (10 μM) did not affect the accumulation of cells in G2 phase and did not affect the decrease in the number of cells in S phase after irradiation. VE-821 (2 and 10 μM) reduced the number of irradiated cells in the G2 phase to the level of non-irradiated cells and increased the number of irradiated cells in S phase, compared to irradiated cells not treated with inhibitors. In the 144 h interval after irradiation with 3 Gy, there was a considerable induction of apoptosis in the VE-821 group (10 μM). The repair of the radiation damage, as observed 72 h after irradiation, was more rapid in the group exposed solely to irradiation and in the group treated with KU55933 (80 and 77 % of cells, respectively, were free of DSBs), whereas in the group incubated with 10 μM VE-821, there were only 61 % of cells free of DSBs. The inhibition of kinase ATR with its specific inhibitor VE-821 resulted in a more pronounced radiosensitizing effect in HL-60 cells as compared to the inhibition of kinase ATM with the inhibitor KU55933. In contrast to KU55933, the VE-821 treatment prevented HL-60 cells from undergoing G2 cell cycle arrest. Taken together, we conclude that the ATR kinase inhibition offers a new possibility of radiosensitization of tumour cells lacking functional protein p53.

Department of Radiobiology Faculty of Health Sciences University of Defence Hradec Králové Brno Czech Republic

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