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

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.

• 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
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 8 Pg. 1789-98 (Aug 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22576130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo(b,d)thiophen-1-yl)acetamide
• Antineoplastic Agents
• Chromones
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• Thiophenes
• DNA-Activated Protein Kinase

Topics

• Animals
• Antineoplastic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Chromones (administration & dosage, pharmacology)
• DNA-Activated Protein Kinase (antagonists & inhibitors)
• Drug Resistance, Neoplasm
• Enzyme Activation
• Enzyme Inhibitors (administration & dosage, pharmacokinetics, pharmacology)
• Female
• Humans
• MCF-7 Cells
• Mice
• Neoplasms (drug therapy, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Thiophenes (administration & dosage, pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays