Department of Frontier Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. matsuhm @ faculty.chiba-u.jp
Oncology. 2010;78(1):62-74. doi: 10.1159/000292362. Epub 2010 Mar 6.
The antitumor mechanism of histone deacetylase (HDAC) inhibitors differs from conventional antitumor agents. HDAC inhibitors may be effective as novel therapeutic agents for esophageal squamous cell carcinoma (ESCC). This study describes the antiproliferative activity of CHAP31, a novel HDAC inhibitor. Furthermore, the molecular mechanism of CHAP31-induced apoptosis was investigated in ESCC.
METHODS/RESULTS: The antitumor activity of CHAP31 was tested in esophageal cancer cell lines (T.Tn and TE2), and potent antitumor activity was observed in vitro and in vivo. In addition, CHAP31 induced apoptosis in esophageal cancer cells. Next, the mechanisms of CHAP31-induced apoptosis were examined using quantitative real-time RT-PCR and Western blotting. No processing of caspase 8 was observed, but CHAP31 induced the cleavage of caspase 9 and up-regulation of the Bax/Bcl-2 protein ratio.
This study provides new and important information on the potent antitumor activity of CHAP31 and the apoptotic pathway induced by CHAP31 in human esophageal cancer cell lines T.Tn and TE2. In contrast to previous reports showing that apoptosis induced by HDAC inhibitors includes the extrinsic pathway, in our study, apoptosis induced by CHAP31 in the human esophageal cell lines T.Tn and TE2 involved only the intrinsic pathway.
组蛋白去乙酰化酶（HDAC）抑制剂的抗肿瘤机制不同于传统的抗肿瘤药物。HDAC 抑制剂可能是治疗食管鳞癌（ESCC）的新型治疗药物。本研究描述了新型 HDAC 抑制剂 CHAP31 的抗增殖活性。此外，还研究了 CHAP31 诱导 ESCC 细胞凋亡的分子机制。
方法/结果：在食管癌细胞系（T.Tn 和 TE2）中检测 CHAP31 的抗肿瘤活性，体外和体内均观察到其具有很强的抗肿瘤活性。此外，CHAP31 诱导食管癌细胞凋亡。接下来，使用实时定量 RT-PCR 和 Western blot 检测 CHAP31 诱导凋亡的机制。未观察到 caspase 8 的加工，但 CHAP31 诱导 caspase 9 的裂解和 Bax/Bcl-2 蛋白比值的上调。
本研究为 CHAP31 的抗肿瘤活性和 CHAP31 在人食管癌细胞系 T.Tn 和 TE2 中诱导的凋亡途径提供了新的重要信息。与先前的报告显示 HDAC 抑制剂诱导的细胞凋亡包括外源性途径不同，在本研究中，CHAP31 在人食管细胞系 T.Tn 和 TE2 中诱导的细胞凋亡仅涉及内源性途径。
