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Further characterisation of the cellular activity of the DNA-PK inhibitor, NU7441, reveals potential cross-talk with homologous recombination

Tavecchio, Michele LU ; Munck, Joanne M; Cano, Celine; Newell, David R and Curtin, Nicola J (2012) In Cancer Chemotherapy and Pharmacology 69(1). p.64-155
Abstract

PURPOSE: Inhibition of DNA repair is emerging as a new therapeutic strategy for cancer treatment. One promising target is DNA-PK, a pivotal kinase in double-strand break repair. The purpose of this study was to further characterise the activity of the DNA-PK inhibitor NU7441, giving some new insights into the biology of DNA-PK.

METHODS: We used NU7441, a potent DNA-PK inhibitor, to evaluate potential pharmacodynamic markers of DNA-PK inhibition, inhibition of DNA repair and chemo- and radio-potentiation in isogenic human cancer cells proficient (M059-Fus1) and deficient (M059 J) in DNA-PK.

RESULTS: NU7441 strongly inhibited DNA-PK in cell lines (IC(50) = 0.3 μM) but only weakly inhibited PI3 K (IC(50) = 7 μM). The only... (More)

PURPOSE: Inhibition of DNA repair is emerging as a new therapeutic strategy for cancer treatment. One promising target is DNA-PK, a pivotal kinase in double-strand break repair. The purpose of this study was to further characterise the activity of the DNA-PK inhibitor NU7441, giving some new insights into the biology of DNA-PK.

METHODS: We used NU7441, a potent DNA-PK inhibitor, to evaluate potential pharmacodynamic markers of DNA-PK inhibition, inhibition of DNA repair and chemo- and radio-potentiation in isogenic human cancer cells proficient (M059-Fus1) and deficient (M059 J) in DNA-PK.

RESULTS: NU7441 strongly inhibited DNA-PK in cell lines (IC(50) = 0.3 μM) but only weakly inhibited PI3 K (IC(50) = 7 μM). The only available anti-phospho-DNA-PK antibody also recognised some phosphoprotein targets of ATM. NU7441 caused doxorubicin- and IR-induced DNA DSBs (measured by γ-H2AX foci) to persist and also slightly decreased homologous recombination activity, as assessed by Rad51 foci. Chemo- and radio-potentiation were induced by NU7441 in M059-Fus-1, but not in DNA-PK-deficient M059 J cells. DNA-PK was highly expressed in a chronic lymphocytic leukaemia sample but undetectable in resting normal human lymphocytes, although it could be induced by PHA-P treatment. In K652 cells, DNA-PK expression was not related to cell cycle phase.

CONCLUSION: These data confirm NU7441 not only as a potent chemo- and radio-sensitiser clinical candidate but also as a powerful tool to study the biology of DNA-PK.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
Animals, Cell Line, Tumor, Chromones, Colonic Neoplasms, DNA Breaks, Double-Stranded, DNA Repair, DNA-Activated Protein Kinase, Doxorubicin, Glioblastoma, Humans, Inhibitory Concentration 50, K562 Cells, Mice, Mice, Inbred BALB C, Mice, Nude, Morpholines, Xenograft Model Antitumor Assays, Journal Article, Research Support, Non-U.S. Gov't
in
Cancer Chemotherapy and Pharmacology
volume
69
issue
1
pages
64 - 155
publisher
Springer
external identifiers
  • scopus:84856700210
ISSN
0344-5704
DOI
10.1007/s00280-011-1662-4
language
English
LU publication?
no
id
c592a09f-ad44-45ec-904c-a7e1066f8e13
date added to LUP
2017-03-07 09:11:05
date last changed
2017-10-08 04:59:42
@article{c592a09f-ad44-45ec-904c-a7e1066f8e13,
  abstract     = {<p>PURPOSE: Inhibition of DNA repair is emerging as a new therapeutic strategy for cancer treatment. One promising target is DNA-PK, a pivotal kinase in double-strand break repair. The purpose of this study was to further characterise the activity of the DNA-PK inhibitor NU7441, giving some new insights into the biology of DNA-PK.</p><p>METHODS: We used NU7441, a potent DNA-PK inhibitor, to evaluate potential pharmacodynamic markers of DNA-PK inhibition, inhibition of DNA repair and chemo- and radio-potentiation in isogenic human cancer cells proficient (M059-Fus1) and deficient (M059 J) in DNA-PK.</p><p>RESULTS: NU7441 strongly inhibited DNA-PK in cell lines (IC(50) = 0.3 μM) but only weakly inhibited PI3 K (IC(50) = 7 μM). The only available anti-phospho-DNA-PK antibody also recognised some phosphoprotein targets of ATM. NU7441 caused doxorubicin- and IR-induced DNA DSBs (measured by γ-H2AX foci) to persist and also slightly decreased homologous recombination activity, as assessed by Rad51 foci. Chemo- and radio-potentiation were induced by NU7441 in M059-Fus-1, but not in DNA-PK-deficient M059 J cells. DNA-PK was highly expressed in a chronic lymphocytic leukaemia sample but undetectable in resting normal human lymphocytes, although it could be induced by PHA-P treatment. In K652 cells, DNA-PK expression was not related to cell cycle phase.</p><p>CONCLUSION: These data confirm NU7441 not only as a potent chemo- and radio-sensitiser clinical candidate but also as a powerful tool to study the biology of DNA-PK.</p>},
  author       = {Tavecchio, Michele and Munck, Joanne M and Cano, Celine and Newell, David R and Curtin, Nicola J},
  issn         = {0344-5704},
  keyword      = {Animals,Cell Line, Tumor,Chromones,Colonic Neoplasms,DNA Breaks, Double-Stranded,DNA Repair,DNA-Activated Protein Kinase,Doxorubicin,Glioblastoma,Humans,Inhibitory Concentration 50,K562 Cells,Mice,Mice, Inbred BALB C,Mice, Nude,Morpholines,Xenograft Model Antitumor Assays,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {1},
  pages        = {64--155},
  publisher    = {Springer},
  series       = {Cancer Chemotherapy and Pharmacology},
  title        = {Further characterisation of the cellular activity of the DNA-PK inhibitor, NU7441, reveals potential cross-talk with homologous recombination},
  url          = {http://dx.doi.org/10.1007/s00280-011-1662-4},
  volume       = {69},
  year         = {2012},
}