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

Research output: Contribution to journalArticle

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) 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.

Details

Authors
  • Joanne M Munck
  • Michael A Batey
  • Yan Zhao
  • Helen Jenkins
  • Caroline J Richardson
  • Celine Cano
  • Michele Tavecchio
  • Jody Barbeau
  • Julia Bardos
  • Liam Cornell
  • Roger J Griffin
  • Keith Menear
  • Andrew Slade
  • Pia Thommes
  • Niall M B Martin
  • David R Newell
  • Graeme C M Smith
  • Nicola J Curtin
External organisations
  • University of Newcastle upon Tyne
Research areas and keywords

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
Original languageEnglish
Pages (from-to)1789-98
JournalMolecular Cancer Therapeutics
Volume11
Issue number8
StatePublished - 2012 Aug
Peer-reviewedYes
Externally publishedYes