Further characterisation of the cellular activity of the DNA-PK inhibitor, NU7441, reveals potential cross-talk with homologous recombination
(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
- Tavecchio, Michele LU ; Munck, Joanne M ; Cano, Celine ; Newell, David R and Curtin, Nicola J
- publishing date
- 2012-01
- 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
-
- pmid:21630086
- 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
- 2024-01-28 14:01:21
@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}},
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}},
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}},
doi = {{10.1007/s00280-011-1662-4}},
volume = {{69}},
year = {{2012}},
}