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

Lookup NU author(s): Dr Joanne Munck, Michael Batey, Dr Yan Zhao, Dr Celine Cano, Dr Michele Tavecchio, Dr Jody Barbeau, Liam Cornell, Professor Roger Griffin, Professor Herbie Newell, Professor Nicola Curtin

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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 IC50 values of 0.019 μmol/L (MCF7 cells) and 0.17 μmol/L (SW620 cells), and PI-3K–mediated AKT phosphorylation with IC50 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.


Publication metadata

Author(s): Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson C, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear KA, Slade A, Thommes P, Martin NMB, Newell DR, Smith GCM, Curtin NJ

Publication type: Article

Journal: Molecular Cancer Therapeutics

Year: 2012

Volume: 11

Issue: 8

Pages: 1789-1798

Print publication date: 01/08/2012

ISSN (print): 1535-7163

ISSN (electronic): 1538-8514

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1535-7163.MCT-11-0535

DOI: 10.1158/1535-7163.MCT-11-0535


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