Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3K
(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.
(Less)
- author
- publishing date
- 2012-08
- type
- Contribution to journal
- publication status
- published
- 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
- in
- Molecular Cancer Therapeutics
- volume
- 11
- issue
- 8
- pages
- 98 - 1789
- publisher
- American Association for Cancer Research
- external identifiers
-
- pmid:22576130
- scopus:84864875154
- ISSN
- 1538-8514
- DOI
- 10.1158/1535-7163.MCT-11-0535
- language
- English
- LU publication?
- no
- id
- 812aa985-f7c3-4069-99fc-2e7763fb7916
- date added to LUP
- 2017-03-07 09:10:37
- date last changed
- 2024-08-19 18:13:52
@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}}, 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}}, 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}}, doi = {{10.1158/1535-7163.MCT-11-0535}}, volume = {{11}}, year = {{2012}}, }