Carcinogenesis Advance Access originally published online on April 7, 2009
Carcinogenesis 2009 30(8):1387-1397; doi:10.1093/carcin/bgp079
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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
1 Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, No. 125 Lih-Der Road, Taipei 112, Taiwan
2 School of Medicine, National Yang-Ming University, No. 155 Sec. 2 Linong Street, Taipei 112, Taiwan
3 Department of Pathology and Laboratory Services, Koo Foundation Sun Yat-Sen Cancer Center, No. 125 Lih-Der Road, Taipei 112, Taiwan
4 ASAN Laboratories, Inc., 10F No. 27, Lane 155 Sec.3 Beishen Road, Shenkeng, Taipei County 222, Taiwan
* To whom correspondence should be addressed. Tel: +886 2 28970011 ext. 1306; Fax: +886 2 28970011 ext. 1310, Email: ylchung{at}kfsyscc.org
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-
H2AX foci, Rad51 foci and phospho-H2AX/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-
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.
Abbreviations: DMBA, 7,12-dimethylbenz[a]anthracene; HDAC, histone deacetylase; miRNA, microRNA; NF-
B, nuclear factor-kappaB; PBS, phosphate-buffered saline; ROS, reactive oxygen species; RT, radiotherapy; RT–PCR, reverse transcription–polymerase chain reaction; TNF-, tumor necrosis factor-
Received January 24, 2009; revised March 24, 2009; accepted March 31, 2009.