Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition

Flatmark Kjersti, Nome, Folkvord Sigurd, Bratland Åse, Rasmussen Heidi, Ellefsen Mali, Fodstad Øystein, Ree, Ree Anne

Description

The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death. Methods Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed. Results In addition to G 2 /M phase arrest following irradiation, the cell lines displayed cell cycle responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G 1 phase cells). In contrast, histone acetylation was associated with complete depletion of the G 1 population of cells with functional p53 but accumulation of both G 1 and G 2 /M populations of cells with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G 2 /M phase kinase. Following pre-treatment with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified. Conclusion In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2006
• Nombre de lectures: 5
• Langue: English

Extrait

Radiation Oncology

BioMedCentral

Open Access Research Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition 1,2 11 1,3 Kjersti Flatmark, Ragnhild V Nome, Sigurd Folkvord, Åse Bratland, 1 41 Heidi Rasmussen, Mali Strand Ellefsen, Øystein Fodstadand 1,3 Anne Hansen Ree*

1 2 Address: Departmentof Tumor Biology, RikshospitaletRadiumhospitalet Medical Center, University of Oslo, 0310 Oslo, Norway,Department 3 of Surgical Oncology, RikshospitaletRadiumhospitalet Medical Center, 0310 Oslo, Norway,Department of Medical Oncology and Radiotherapy, 4 RikshospitaletRadiumhospitalet Medical Center, 0310 Oslo, Norway andDepartment of Radiation Biology, RikshospitaletRadiumhospitalet Medical Center, 0310 Oslo, Norway Email: Kjersti Flatmark  [e-mail]; Ragnhild V Nome  [e-mail]; Sigurd Folkvord  [e-mail]; Åse Bratland  [e-mail]; Heidi Rasmussen  [e-mail]; Mali Strand Ellefsen  [e-mail]; Øystein Fodstad  [e-mail]; Anne Hansen Ree*  [e-mail] * Corresponding author

Published: 03 August 2006Received: 20 June 2006 Accepted: 03 August 2006 Radiation Oncology2006,1:25 doi:10.1186/1748-717X-1-25 This article is available from: http://www.ro-journal.com/content/1/1/25 © 2006 Flatmark et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Background:The tumor response to preoperative radiotherapy of locally advanced rectal cancer varies greatly, warranting the use of experimental models to assay the efficacy of molecular targeting agents in rectal cancer radiosensitization. Histone deacetylase (HDAC) inhibitors, agents that cause hyperacetylation of histone proteins and thereby remodeling of chromatin structure, may override cell cycle checkpoint responses to DNA damage and amplify radiation-induced tumor cell death. Methods:Human colorectal carcinoma cell lines were exposed to ionizing radiation and HDAC inhibitors, and cell cycle profiles and regulatory factors, as well as clonogenicity, were analyzed. Results:In addition to G /M phase arrest following irradiation, the cell lines displayed cell cycle 2 responses typical for either intact or defective p53 function (the presence or absence, respectively, of radiation-induced expression of the cell cycle inhibitor p21 and subsequent accumulation of G 1 phase cells). In contrast, histone acetylation was associated with complete depletion of the G 1 population of cells with functional p53 but accumulation of both Gand G /M populations of cells 1 2 with defective p53. The cellular phenotypes upon HDAC inhibition were consistent with the observed repression of Polo-like kinase-1, a regulatory G/M phase kinase. Following pre-treatment 2 with HDAC inhibitors currently undergoing clinical investigation, the inhibitory effect of ionizing radiation on clonogenicity was significantly amplified. Conclusion:In these experimental models, HDAC inhibition sensitized the tumor cells to ionizing radiation, which is in accordance with the concept of increased probability of tumor cell death when chromatin structure is modified.

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