title: C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe.
abstract: OBJECTIVE
  Chromatin remodeling through histone modifications, including acetylation, plays an important role in the appropriate response to DNA damage induced by ionizing radiation (IR). Here we investigated the radiosensitizing effect of C646, a selective small molecule inhibitor of p300 histone acetyltransferase, and explored the underlying mechanisms.
  
  
  METHODS
  A549, H157 and H460 human non-small cell lung carcinoma (NSCLC) cells, and HFL-III human lung fibroblasts were assessed by clonogenic survival assay. Apoptosis and necrosis were assessed by annexin V staining. Senescence was assessed by Senescence-associated β-galactosidase staining. Mitotic catastrophe was assessed by evaluating nuclear morphology with DAPI staining. Cell cycle profiles were analyzed by flow cytometry. Protein expression was analyzed by immunoblotting.
  
  
  RESULTS
  C646 sensitized A549, H460 and H157 cells to IR with a dose enhancement ratio at 10% surviving fraction of 1.4, 1.2 and 1.2, respectively. C646 did not radiosensitize HFL-III cells. In A549 cells, but not in HFL-III cells, C646 (i) enhanced mitotic catastrophe but not apoptosis, necrosis, or senescence after IR; (ii) increased the hyperploid cell population after IR; and (iii) suppressed the phosphorylation of CHK1 after IR.
  
  
  CONCLUSIONS
  C646 radiosensitizes NSCLC cells by enhancing mitotic catastrophe through the abrogation of G2 checkpoint maintenance.
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan; Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oike
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Komachi
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ogiwara
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Napapat
authors.initials: N
authors.lastname: Amornwichet
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Saitoh
authors.affiliation: Gunma University Heavy Ion Medical Center, Maebashi, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Torikai
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Nobuteru
authors.initials: N
authors.lastname: Kubo
authors.affiliation: Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Japan. Electronic address: tkkohno@ncc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D001565:Benzoates / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008938:Mitosis / Q000187:drug effects*; D009578:Nitrobenzenes; D011494:Protein Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D047069:Pyrazolones; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
chemical_list: C584509:4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid; D001565:Benzoates; D009578:Nitrobenzenes; D011720:Pyrazoles; D047069:Pyrazolones; D011838:Radiation-Sensitizing Agents; D051548:Histone Acetyltransferases; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: G2 checkpoint; Histone acetyltransferase; Mitotic catastrophe; Radiosensitizer; p300