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  2. C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe

C646, a selective small molecule inhibitor of histone acetyltransferase p300, radiosensitizes lung cancer cells by enhancing mitotic catastrophe

  • Radiother Oncol. 2014 May;111(2):222-7. doi: 10.1016/j.radonc.2014.03.015.
Takahiro Oike 1 Mayumi Komachi 2 Hideaki Ogiwara 3 Napapat Amornwichet 2 Yuka Saitoh 2 Kohta Torikai 4 Nobuteru Kubo 2 Takashi Nakano 2 Takashi Kohno 5
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan; Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Japan.
  • 2 Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
  • 3 Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Japan.
  • 4 Gunma University Heavy Ion Medical Center, Maebashi, Japan.
  • 5 Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Japan. Electronic address: tkkohno@ncc.go.jp.
Abstract

Background and purpose: 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.

Materials and 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.

Keywords

G2 checkpoint; Histone acetyltransferase; Mitotic catastrophe; Radiosensitizer; p300.

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