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Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K

Munck, Joanne M; Batey, Michael A; Zhao, Yan; Jenkins, Helen; Richardson, Caroline J; Cano, Celine; Tavecchio, Michele LU ; Barbeau, Jody; Bardos, Julia and Cornell, Liam, et al. (2012) In Molecular Cancer Therapeutics 11(8). p.98-1789
Abstract

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK autophosphorylation with IC(50) values of 0.019 μmol/L (MCF7 cells) and 0.17 μmol/L (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC(50) values of 0.039 μmol/L (MCF7 cells)... (More)

DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK autophosphorylation with IC(50) values of 0.019 μmol/L (MCF7 cells) and 0.17 μmol/L (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC(50) values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells). Five-day exposure to 1 μmol/L KU-0060648 inhibited cell proliferation by more than 95% in MCF7 cells but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor for at least 4 hours at nontoxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumor growth delay in both in SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof-of-principle in vitro and in vivo chemosensitization with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors.

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keywords
Animals, Antineoplastic Agents, Cell Line, Tumor, Chromones, DNA-Activated Protein Kinase, Drug Resistance, Neoplasm, Enzyme Activation, Enzyme Inhibitors, Female, Humans, MCF-7 Cells, Mice, Neoplasms, Phosphatidylinositol 3-Kinases, Thiophenes, Tumor Burden, Xenograft Model Antitumor Assays, Journal Article, Research Support, Non-U.S. Gov't
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Molecular Cancer Therapeutics
volume
11
issue
8
pages
98 - 1789
publisher
American Association for Cancer Research
external identifiers
  • scopus:84864875154
ISSN
1538-8514
DOI
10.1158/1535-7163.MCT-11-0535
language
English
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no
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812aa985-f7c3-4069-99fc-2e7763fb7916
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2017-03-07 09:10:37
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@article{812aa985-f7c3-4069-99fc-2e7763fb7916,
  abstract     = {<p>DNA double-strand breaks (DSB) are the most cytotoxic lesions induced by topoisomerase II poisons. Nonhomologous end joining (NHEJ) is a major pathway for DSB repair and requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK catalytic subunit (DNA-PKcs) is structurally similar to PI-3K, which promotes cell survival and proliferation and is upregulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. KU-0060648 was investigated in a panel of human breast and colon cancer cells. The compound inhibited cellular DNA-PK autophosphorylation with IC(50) values of 0.019 μmol/L (MCF7 cells) and 0.17 μmol/L (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC(50) values of 0.039 μmol/L (MCF7 cells) and more than 10 μmol/L (SW620 cells). Five-day exposure to 1 μmol/L KU-0060648 inhibited cell proliferation by more than 95% in MCF7 cells but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were sufficient for in vitro growth inhibition and chemosensitization were maintained within the tumor for at least 4 hours at nontoxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumor growth delay in both in SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof-of-principle in vitro and in vivo chemosensitization with KU-0060648 justifies further evaluation of dual DNA-PK and PI-3K inhibitors.</p>},
  author       = {Munck, Joanne M and Batey, Michael A and Zhao, Yan and Jenkins, Helen and Richardson, Caroline J and Cano, Celine and Tavecchio, Michele and Barbeau, Jody and Bardos, Julia and Cornell, Liam and Griffin, Roger J and Menear, Keith and Slade, Andrew and Thommes, Pia and Martin, Niall M B and Newell, David R and Smith, Graeme C M and Curtin, Nicola J},
  issn         = {1538-8514},
  keyword      = {Animals,Antineoplastic Agents,Cell Line, Tumor,Chromones,DNA-Activated Protein Kinase,Drug Resistance, Neoplasm,Enzyme Activation,Enzyme Inhibitors,Female,Humans,MCF-7 Cells,Mice,Neoplasms,Phosphatidylinositol 3-Kinases,Thiophenes,Tumor Burden,Xenograft Model Antitumor Assays,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {8},
  pages        = {98--1789},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Therapeutics},
  title        = {Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K},
  url          = {http://dx.doi.org/10.1158/1535-7163.MCT-11-0535},
  volume       = {11},
  year         = {2012},
}