Radiosensitization by SAHA in experimental colorectal carcinoma models-in vivo effects and relevance of histone acetylation status.
OBJECTIVE
Histone deacetylase inhibitors are being evaluated as antitumor agents in ongoing clinical trials, and promising preclinical results, combined with favorable toxicity profiles, have rendered the drugs as interesting candidates for combination with other treatment modalities, such as radiotherapy. The aim of the present study was to evaluate the radiosensitizing properties of suberoylanilide hydroxamic acid (SAHA) and the possible requirement of histone hyperacetylation at radiation exposure.


METHODS
Radiosensitization by SAHA was assessed in a colorectal carcinoma cell line and in two colorectal xenograft models by analysis of clonogenic survival and tumor growth delay, respectively. Histone acetylation status at radiation exposure was evaluated by Western blot.


RESULTS
In vitro, radiosensitization was demonstrated when cells were preincubated with SAHA, and, in the xenografts, tumor growth was delayed when the mice were treated with fractionated radiation combined with daily SAHA injections compared with radiation alone. Surprisingly, the SAHA-dependent growth delay was still present when radiation was delivered at restored baseline acetylation levels compared with maximal histone hyperacetylation.


CONCLUSIONS
SAHA was an effective radiosensitizer in experimental colorectal carcinoma models, suggesting that histone deacetylase inhibition might constitute a valuable supplement to current multimodal treatment strategies in rectal cancer. The presence of histone hyperacetylation at radiation was not required to obtain an increased radiation response, questioning the validity of using histone hyperacetylation as a molecular marker for radiosensitivity.
Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway.
Sigurd
S
Folkvord
Anne Hansen
AH
Ree
Torbjørn
T
Furre
Thomas
T
Halvorsen
Kjersti
K
Flatmark
D000107:Acetylation; D000818:Animals; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D045325:HCT116 Cells; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D011897:Random Allocation; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D014410:Tumor Stem Cell Assay; D000077337:Vorinostat
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D011838:Radiation-Sensitizing Agents; D000077337:Vorinostat