Epigenetic therapy using the histone deacetylase inhibitor for increasing therapeutic gain in oral cancer: prevention of radiation-induced oral mucositis and inhibition of chemical-induced oral carcinogenesis.
In addition to genetic changes, epigenetic aberrations also play important roles in radiation- and chemical-induced disorders and carcinogenesis. The present study investigated whether epigenetic therapy with a histone deacetylase (HDAC) inhibitor has dual benefits for radiation-induced oral mucositis and chemical-induced oral carcinogenesis, which should be treated at the same time. The HDAC inhibitor phenylbutyrate was first tested to determine if it influences DNA damage repair and survival in irradiated normal cells in vitro by investigating the patterns and dynamics of phospho-gammaH2AX foci, Rad51 foci and phospho-gammaH2AX/Rad51 colocalization and using the comet and clonogenic assays. Oral mucositis or carcinogenesis was induced in hamsters using radiation or 7,12-dimethylbenz[a]anthracene (DMBA) irritation to the cheek pouch. The ability of phenylbutyrate formed in proper carriers to prevent radiation-induced oral mucositis and inhibit chemical-induced oral carcinogenesis was assessed. The treated or untreated irradiated or DMBA-irritated oral tissues or mucosal epithelia were subjected to the studies of histology, immunohistochemistry, gene expression, comet assay, HDAC activity or oxidative stress. We found that phenylbutyrate promoted DNA repair and survival in normal cells after radiation. Compared with blank or vehicle-treated hamsters, the irradiated mucosa treated with phenylbutyrate had significantly lower oxidative stress and tumor necrosis factor-alpha expression and less severe oral mucositis of a shorter duration. A reduction of the oral tumor incidence, burden and progression by phenylbutyrate correlated with the suppression of oncomiRs and Rad51 overexpression, the upregulation of differentiation markers and the decrease of intracellular HDAC activity and oxidative stress during DMBA-induced oral carcinogenesis. Thus, epigenetic therapy using the HDAC inhibitor as an adjuvant to radiotherapy for chemical-induced oral cancer may provide a promising strategy combining the prevention of radiation-induced oral mucositis and the inhibition of oral carcinogenesis.
Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, No. 125 Lih-Der Road, Taipei 112, Taiwan. ylchung@kfsyscc.org
Yih-Lin
YL
Chung
Ming-Yuan
MY
Lee
Newman N M
NN
Pui
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000107:Acetylation / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008647:Mesocricetus; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D010654:Phenylbutyrates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D011832:Radiation Injuries / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013280:Stomatitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010654:Phenylbutyrates; D012333:RNA, Messenger; D015127:9,10-Dimethyl-1,2-benzanthracene; C075773:4-phenylbutyric acid; D051135:Rad51 Recombinase; D006655:Histone Deacetylases