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DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and doxorubicin

Ciszewski, Wojciech M; Tavecchio, Michele LU ; Dastych, Jarosław and Curtin, Nicola J (2014) In Breast Cancer Research and Treatment 143(1). p.47-55
Abstract

DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double-strand breaks (DSBs) that are probably the most deleterious form of DNA damage. Inhibition of DNA-PK has been considered as an attractive approach to decrease resistance to therapeutically induced DNA DSBs. Ionizing radiation (IR) and doxorubicin, which induce DSBs, are used in the treatment of breast cancer. We determined the cellular concentration of DNA-PK and other DSB-activated kinases: ATM and ATR and the effect of DNA-PK inhibition by NU7441 on DNA repair, cell cycle, and survival after IR or doxorubicin treatment in three human breast cancer cell lines (MCF-7, MDA-MB-231, and T47D) representing different breast cancer subtypes. T47D cells had the... (More)

DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double-strand breaks (DSBs) that are probably the most deleterious form of DNA damage. Inhibition of DNA-PK has been considered as an attractive approach to decrease resistance to therapeutically induced DNA DSBs. Ionizing radiation (IR) and doxorubicin, which induce DSBs, are used in the treatment of breast cancer. We determined the cellular concentration of DNA-PK and other DSB-activated kinases: ATM and ATR and the effect of DNA-PK inhibition by NU7441 on DNA repair, cell cycle, and survival after IR or doxorubicin treatment in three human breast cancer cell lines (MCF-7, MDA-MB-231, and T47D) representing different breast cancer subtypes. T47D cells had the highest expression of DNA-PKcs, ATM, and ATR and the most rapid rate of DNA DSB repair. IR caused a 10- to 16-fold increase in DNA-PK activity and two to threefold induction of ATM in all 3 cell lines. NU7441 inhibited IR-induced DNA-PK activity in all cell lines with IC50s in the range 0.17-0.25 μM. NU7441 retarded the repair of DSB and significantly increased the sensitivity of all cell lines to IR (4- to 12-fold) and doxorubicin (3- to 13-fold). The greatest sensitization by NU7441 was observed in MDA-MB-231 cells. NU7441 affected the cell cycle distribution in all studied cell lines; increasing accumulation of cells in G2/M phase after DNA damage. Our data indicate that DNA-PK might be an effective target for chemo- and radio-potentiation in breast cancer and suggest that further development of DNA-PK inhibitors for clinical use is warranted.

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publishing date
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publication status
published
keywords
Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms, Cell Cycle, Cell Line, Tumor, Chromones, DNA Breaks, Double-Stranded, DNA-Activated Protein Kinase, Doxorubicin, Drug Resistance, Neoplasm, Female, Humans, MCF-7 Cells, Morpholines, Phosphorylation, Protein Kinase Inhibitors, Radiation Tolerance, Radiation, Ionizing, Journal Article, Research Support, Non-U.S. Gov't
in
Breast Cancer Research and Treatment
volume
143
issue
1
pages
9 pages
publisher
Springer
external identifiers
  • scopus:84892799067
ISSN
1573-7217
DOI
10.1007/s10549-013-2785-6
language
English
LU publication?
no
id
5b4182e4-9590-4ab1-9fd2-bb99d07635a3
date added to LUP
2017-03-07 09:09:12
date last changed
2017-10-22 05:27:50
@article{5b4182e4-9590-4ab1-9fd2-bb99d07635a3,
  abstract     = {<p>DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double-strand breaks (DSBs) that are probably the most deleterious form of DNA damage. Inhibition of DNA-PK has been considered as an attractive approach to decrease resistance to therapeutically induced DNA DSBs. Ionizing radiation (IR) and doxorubicin, which induce DSBs, are used in the treatment of breast cancer. We determined the cellular concentration of DNA-PK and other DSB-activated kinases: ATM and ATR and the effect of DNA-PK inhibition by NU7441 on DNA repair, cell cycle, and survival after IR or doxorubicin treatment in three human breast cancer cell lines (MCF-7, MDA-MB-231, and T47D) representing different breast cancer subtypes. T47D cells had the highest expression of DNA-PKcs, ATM, and ATR and the most rapid rate of DNA DSB repair. IR caused a 10- to 16-fold increase in DNA-PK activity and two to threefold induction of ATM in all 3 cell lines. NU7441 inhibited IR-induced DNA-PK activity in all cell lines with IC50s in the range 0.17-0.25 μM. NU7441 retarded the repair of DSB and significantly increased the sensitivity of all cell lines to IR (4- to 12-fold) and doxorubicin (3- to 13-fold). The greatest sensitization by NU7441 was observed in MDA-MB-231 cells. NU7441 affected the cell cycle distribution in all studied cell lines; increasing accumulation of cells in G2/M phase after DNA damage. Our data indicate that DNA-PK might be an effective target for chemo- and radio-potentiation in breast cancer and suggest that further development of DNA-PK inhibitors for clinical use is warranted.</p>},
  author       = {Ciszewski, Wojciech M and Tavecchio, Michele and Dastych, Jarosław and Curtin, Nicola J},
  issn         = {1573-7217},
  keyword      = {Ataxia Telangiectasia Mutated Proteins,Breast Neoplasms,Cell Cycle,Cell Line, Tumor,Chromones,DNA Breaks, Double-Stranded,DNA-Activated Protein Kinase,Doxorubicin,Drug Resistance, Neoplasm,Female,Humans,MCF-7 Cells,Morpholines,Phosphorylation,Protein Kinase Inhibitors,Radiation Tolerance,Radiation, Ionizing,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {1},
  pages        = {47--55},
  publisher    = {Springer},
  series       = {Breast Cancer Research and Treatment},
  title        = {DNA-PK inhibition by NU7441 sensitizes breast cancer cells to ionizing radiation and doxorubicin},
  url          = {http://dx.doi.org/10.1007/s10549-013-2785-6},
  volume       = {143},
  year         = {2014},
}