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
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
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DOI：
10.1093/carcin/bgp079
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发表时间：
2009-08-01
期刊：
影响因子：
4.7
通讯作者：
Pui, Newman N. M.
中科院分区：
文献类型：
--
作者：
Chung, Yih-Lin;Lee, Ming-Yuan;Pui, Newman N. M.
除遗传变化外，表观遗传畸变在辐射和化学品诱发的疾病和致癌作用中也发挥重要作用。本研究调查是否表观遗传治疗与组蛋白脱乙酰酶（HDAC）抑制剂有双重好处的放射性诱导的口腔粘膜炎和化学诱导的口腔癌，这应该在同一时间进行治疗。首先测试HDAC抑制剂苯丁酸盐以通过研究磷酸-γ H2 AX焦点、Rad 51焦点和磷酸-γ H2 AX/Rad 51共定位的模式和动力学并使用彗星和克隆形成测定来确定其是否影响体外辐射的正常细胞中的DNA损伤修复和存活。使用辐射或7，12-二甲基苯并[a]蒽（DMBA）刺激颊囊，在仓鼠中诱导口腔粘膜炎或癌变。评价了在适当载体中形成的苯丁酸盐预防辐射诱导的口腔粘膜炎和抑制化学诱导的口腔癌发生的能力。对处理或未处理的经照射或DMBA刺激的口腔组织或粘膜上皮进行组织学、免疫组织化学、基因表达、彗星试验、HDAC活性或氧化应激的研究。我们发现，苯丁酸促进辐射后正常细胞的DNA修复和存活。与空白或溶剂处理的仓鼠相比，用苯丁酸盐处理的辐照粘膜具有显著较低的氧化应激和肿瘤坏死因子-α表达，并且持续时间较短的严重口腔粘膜炎较轻。苯丁酸盐降低口腔肿瘤发病率、负荷和进展与抑制oncomiRs和Rad 51过表达、上调分化标志物以及DMBA诱导的口腔癌发生过程中细胞内HDAC活性和氧化应激降低相关。因此，使用HDAC抑制剂作为化学诱导的口腔癌的放射治疗的辅助剂的表观遗传疗法可以提供结合预防放射诱导的口腔粘膜炎和抑制口腔癌发生的有希望的策略。
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-gamma H2AX foci, Rad51 foci and phospho-gamma 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-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.