Hoshino Isamu, Matsubara Hisahiro, Akutsu Yasunori, Nishimori Takanori, Yoneyama Yasuo, Murakami Kentaro, Sakata Haruhito, Matsushita Kazuyuki, Komatsu Aki, Brooks Ryan, Ochiai Takenori
Department of Frontier Surgery, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.
Anticancer Res. 2008 Mar-Apr;28(2A):665-71.
Recently, the use of histone deacetylase inhibitors (HDACI) with gene therapy has been shown to improve the effect of this therapy. The effectiveness of one of the novel HDACIs, FK228, was examined in adenovirus-mediated p53 gene therapy of esophageal squamous cell carcinoma (ESCC).
The expression levels of coxsackie and adenovirus receptor (CAR) in ESCC patients were examined immunohistochemically. CAR induction by FK228 in ESCC cells was analyzed by real-time PCR and Western blotting. The efficiencies of adenoviral transduction treated with FK228 were determined using AV1.0CMV-betagal. The acetylation of p53 protein was detected by Western blotting.
CAR expression was reduced in some tumor specimens compared to that in normal specimens. CAR expression was increased by FK228 in both in vitro and in vivo experiments. FK228 improved the efficiency of adenovirus infection. Acetylated p53 protein was increased in a dose- and a time-dependent manner.
Our findings suggest that FK228 has a potent ability to augment the effect of adenovirus-mediated p53 gene therapy in ESCC cells.
最近，已证明组蛋白去乙酰化酶抑制剂（HDACI）与基因治疗联合使用可提高该疗法的效果。在食管鳞状细胞癌（ESCC）的腺病毒介导的p53基因治疗中，对新型HDACIs之一FK228的有效性进行了研究。
采用免疫组织化学方法检测ESCC患者中柯萨奇病毒和腺病毒受体（CAR）的表达水平。通过实时PCR和蛋白质印迹法分析FK228在ESCC细胞中对CAR的诱导作用。使用AV1.0CMV-β半乳糖苷酶测定经FK228处理的腺病毒转导效率。通过蛋白质印迹法检测p53蛋白的乙酰化情况。
与正常标本相比，一些肿瘤标本中CAR表达降低。在体外和体内实验中，FK228均可增加CAR表达。FK228提高了腺病毒感染效率。乙酰化p53蛋白呈剂量和时间依赖性增加。
我们的研究结果表明，FK228具有增强腺病毒介导的p53基因治疗对ESCC细胞作用的强大能力。
