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Title: Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining

Abstract

Purpose: Non-homologous end joining (NHEJ), a major pathway used to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through the acetylation of histones by histone acetyltransferases (HATs). However, the effect of compounds with HAT inhibitory activities on the DNA damage response (DDR), including the NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells, remains largely unclear. Here, we investigated whether garcinol, a HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR, and whether it can be used for radiosensitization. Methods and Materials: The following assays were used to examine the effect of garcinol on the inhibition of DSB repair, including the following: a conventional neutral comet assay; a cell-based assay recently developed by us, in which NHEJ repair of DSBs on chromosomal DNA was evaluated; the micrococcal nuclease sensitivity assay; and immunoblotting for autophosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We assessed the effect of garcinol on the cell cycle checkpoint after IR treatment by analyzing the phosphorylation levels of checkpoint kinases CHK1 and CHK2 and histone H3, and by cell cycle profile analysis using flow cytometry. The radiosensitizingmore » effect of garcinol was assessed by a clonogenic survival assay, whereas its effects on apoptosis and senescence were examined by annexin V and senescence-associated {beta}-galactosidase (SA-{beta}-Gal) staining, respectively. Results: We found that garcinol inhibits DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with dose enhancement ratios (at 10% surviving fraction) of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. Conclusion: These results suggest that garcinol is a radiosensitizer that inhibits NHEJ and facilitates senescence without impairing activation of the cell cycle checkpoint.« less

Authors:
 [1];  [2];  [2];  [3];  [4];  [5];  [1];  [3]
  1. Division of Multistep Carcinogenesis, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan)
  2. (Japan)
  3. Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan)
  4. Gunma University Heavy Ion Medical Center, Maebashi, Gunma (Japan)
  5. Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma (Japan)
Publication Date:
OSTI Identifier:
22149603
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 84; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; 62 RADIOLOGY AND NUCLEAR MEDICINE; ACETYLATION; APOPTOSIS; CARCINOMAS; CELL CYCLE; CHROMATIN; DNA; DOSES; GALACTOSIDASE; HISTONES; IONIZING RADIATIONS; LUNGS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; RADIOSENSITIVITY; REPAIR; STRAND BREAKS

Citation Formats

Oike, Takahiro, Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Ogiwara, Hideaki, Torikai, Kohta, Nakano, Takashi, Yokota, Jun, and Kohno, Takashi, E-mail: tkkohno@ncc.go.jp. Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining. United States: N. p., 2012. Web. doi:10.1016/J.IJROBP.2012.01.017.
Oike, Takahiro, Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Ogiwara, Hideaki, Torikai, Kohta, Nakano, Takashi, Yokota, Jun, & Kohno, Takashi, E-mail: tkkohno@ncc.go.jp. Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining. United States. doi:10.1016/J.IJROBP.2012.01.017.
Oike, Takahiro, Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Ogiwara, Hideaki, Torikai, Kohta, Nakano, Takashi, Yokota, Jun, and Kohno, Takashi, E-mail: tkkohno@ncc.go.jp. Thu . "Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining". United States. doi:10.1016/J.IJROBP.2012.01.017.
@article{osti_22149603,
title = {Garcinol, a Histone Acetyltransferase Inhibitor, Radiosensitizes Cancer Cells by Inhibiting Non-Homologous End Joining},
author = {Oike, Takahiro and Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo and Department of Radiation Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma and Ogiwara, Hideaki and Torikai, Kohta and Nakano, Takashi and Yokota, Jun and Kohno, Takashi, E-mail: tkkohno@ncc.go.jp},
abstractNote = {Purpose: Non-homologous end joining (NHEJ), a major pathway used to repair DNA double-strand breaks (DSBs) generated by ionizing radiation (IR), requires chromatin remodeling at DSB sites through the acetylation of histones by histone acetyltransferases (HATs). However, the effect of compounds with HAT inhibitory activities on the DNA damage response (DDR), including the NHEJ and cell cycle checkpoint, as well as on the radiosensitivity of cancer cells, remains largely unclear. Here, we investigated whether garcinol, a HAT inhibitor found in the rinds of Garcinia indica fruit (called mangosteens), has effects on DDR, and whether it can be used for radiosensitization. Methods and Materials: The following assays were used to examine the effect of garcinol on the inhibition of DSB repair, including the following: a conventional neutral comet assay; a cell-based assay recently developed by us, in which NHEJ repair of DSBs on chromosomal DNA was evaluated; the micrococcal nuclease sensitivity assay; and immunoblotting for autophosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). We assessed the effect of garcinol on the cell cycle checkpoint after IR treatment by analyzing the phosphorylation levels of checkpoint kinases CHK1 and CHK2 and histone H3, and by cell cycle profile analysis using flow cytometry. The radiosensitizing effect of garcinol was assessed by a clonogenic survival assay, whereas its effects on apoptosis and senescence were examined by annexin V and senescence-associated {beta}-galactosidase (SA-{beta}-Gal) staining, respectively. Results: We found that garcinol inhibits DSB repair, including NHEJ, without affecting cell cycle checkpoint. Garcinol radiosensitized A549 lung and HeLa cervical carcinoma cells with dose enhancement ratios (at 10% surviving fraction) of 1.6 and 1.5, respectively. Cellular senescence induced by IR was enhanced by garcinol. Conclusion: These results suggest that garcinol is a radiosensitizer that inhibits NHEJ and facilitates senescence without impairing activation of the cell cycle checkpoint.},
doi = {10.1016/J.IJROBP.2012.01.017},
journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 3,
volume = 84,
place = {United States},
year = {2012},
month = {11}
}