title: 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.affiliation: Medical School, Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Munck
authors.forename: Michael A
authors.initials: MA
authors.lastname: Batey
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Helen
authors.initials: H
authors.lastname: Jenkins
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Richardson
authors.forename: Celine
authors.initials: C
authors.lastname: Cano
authors.forename: Michele
authors.initials: M
authors.lastname: Tavecchio
authors.forename: Jody
authors.initials: J
authors.lastname: Barbeau
authors.forename: Julia
authors.initials: J
authors.lastname: Bardos
authors.forename: Liam
authors.initials: L
authors.lastname: Cornell
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: Keith
authors.initials: K
authors.lastname: Menear
authors.forename: Andrew
authors.initials: A
authors.lastname: Slade
authors.forename: Pia
authors.initials: P
authors.lastname: Thommes
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.forename: Graeme C M
authors.initials: GC
authors.lastname: Smith
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology*; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C576809:2-(4-ethylpiperazin-1-yl)-N-(4-(2-morpholino-4-oxo-4H-chromen-8-yl)dibenzo(b,d)thiophen-1-yl)acetamide; D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013876:Thiophenes; D051747:DNA-Activated Protein Kinase