Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells.
HDAC inhibitors induce histone hyperacetylation by a relative increase of histone acetyltransferase activity. Histone hyperacetylation may affect chromatin structure and susceptibility to DNA-damaging stress, such as IR. We here investigate whether these inhibitors can radiosensitize human gastric MKN45 and colorectal DLD1 adenocarcinoma cells. In both cells, FK228 pretreatment at minimally toxic concentrations clearly augmented IR-induced cell death, DNA fragmentation and caspase-3/-8 activation. In contrast, 5-FU did not clearly augment IR-induced cell death and caspase-3 activation. FK228 increased expression of proapoptotic BH3-only Bim proteins, and gene transfer-mediated overexpression of Bimalpha radiosensitized DLD1 cells. These data suggest that the FK228-mediated increase of Bim expression may at least partially contribute to its augmentation of radiation-induced apoptosis. However, FK228 did not distinctly affect IR-induced phosphorylation of H2AX, which is an initial event followed by DNA damage. FK228 strongly augmented IR-induced growth suppression of MKN45 tumor xenografts. In addition, other HDAC inhibitors, MS275 and CBHA, similarly augmented IR-induced cell death in both cell types. Our results suggest that these HDAC inhibitors may enhance the efficacy of radiation therapy in gastrointestinal cancer cells.
Zhang
Yubin
Y
First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.
Adachi
Masaaki
M
Zhao
Xudong
X
Kawamura
Rina
R
Imai
Kohzoh
K
D000230:Adenocarcinoma / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides / Q000494:pharmacology*; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology*; D047630:Depsipeptides; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005770:Gastrointestinal Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001549:Benzamides; D002352:Carrier Proteins; D002934:Cinnamates; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D008565:Membrane Proteins; D010456:Peptides, Cyclic; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D012333:RNA, Messenger; D011838:Radiation-Sensitizing Agents; C111238:carboxycinnamic acid bishydroxamide; C118739:entinostat; C087123:romidepsin