Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition.
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(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 G1 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.


CONCLUSIONS
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.
Flatmark
Kjersti
K
Department of Tumor Biology, Rikshospitalet-Radiumhospitalet Medical Center, University of Oslo, 0310 Oslo, Norway. kjersti.flatmark@labmed.uio.no
Nome
Ragnhild V
RV
Folkvord
Sigurd
S
Bratland
Ase
A
Rasmussen
Heidi
H
Ellefsen
Mali Strand
MS
Fodstad
Øystein
Ø
Ree
Anne Hansen
AH
D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000532:radiotherapy*; D004249:DNA Damage; D016158:Genes, p53; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry; D006657:Histones / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010641:Phenotype; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011878:Radiotherapy / Q000379:methods
D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D011838:Radiation-Sensitizing Agents; D006655:Histone Deacetylases