The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells.
The histone deacetylase inhibitor FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway in small cell lung cancer cells.
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DOI：
10.1158/1535-7163.1397.3.11
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发表时间：
2004-11
影响因子：
5.7
通讯作者：
S. Doi;H. Soda;M. Oka;J. Tsurutani;T. Kitazaki;Yoichi Nakamura;M. Fukuda;Yasuaki Yamada;S. Kam
中科院分区：
文献类型：
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作者：
S. Doi;H. Soda;M. Oka;J. Tsurutani;T. Kitazaki;Yoichi Nakamura;M. Fukuda;Yasuaki Yamada;S. Kam
组蛋白去乙酰化酶抑制剂调节靶基因的转录，代表了一类新的抗癌药物。组蛋白去乙酰化酶抑制剂FR 901228已被报道在各种恶性肿瘤包括小细胞肺癌（SCLC）中显示出体外抗增殖和凋亡作用;然而，其潜在机制尚未完全了解。BCL-2和BCL-XL是抗凋亡蛋白，已报道其过表达赋予对抗癌剂的抗性。高水平的BCL-2和BCL-XL经常在SCLC肿瘤中表达。本研究旨在阐明FR 901228在体外诱导SCLC细胞凋亡的途径。FR 901228处理24小时后在三种SCLC细胞系中诱导凋亡。FR 901228激活caspase-9和caspase-3，但不激活caspase-8，caspase-3抑制剂Z-DEVD-favorite阻断FR 901228的细胞毒性。FR 901228通过蛋白合成下调bcl-2和bcl-xL mRNA的表达，抑制BCL-2和BCL-XL蛋白的表达。此外，bcl-2反义寡核苷酸与FR 901228的组合增强FR 901228诱导的caspase-3活性和细胞毒性。这些发现表明，FR 901228诱导caspase依赖性细胞凋亡通过线粒体途径，而不是死亡受体途径。考虑到BCL-2和BCL-XL对多药耐药的可能贡献，FR 901228是治疗难治性和原发性SCLC肿瘤的有希望的药物。
Histone deacetylase inhibitors modulate the transcription of target genes and represent a new class of anticancer agents. The histone deacetylase inhibitor FR901228 has been reported to show antiproliferative and apoptotic effects in various malignancies including small cell lung cancer (SCLC) in vitro; however, the underlying mechanism is not fully understood. BCL-2 and BCL-XL are antiapoptotic proteins, of which overexpression has been reported to confer resistance to anticancer agents. High levels of BCL-2 and BCL-XL are frequently expressed in SCLC tumors. The present study was designed to clarify the apoptotic pathway of FR901228 in SCLC cells in vitro. FR901228 induced apoptosis in three SCLC cell lines after 24 hours of treatment. FR901228 activated caspase-9 and caspase-3 but not caspase-8, and the caspase-3 inhibitor Z-DEVD-fmk blocked the cytotoxicity of FR901228. FR901228 down-regulated the expression of bcl-2 and bcl-xL mRNA through de novo protein synthesis and suppressed the expression of BCL-2 and BCL-XL proteins. In addition, the combination of bcl-2 antisense oligonucleotides with FR901228 enhanced FR901228-induced caspase-3 activity and cytotoxicity. These findings suggest that FR901228 induces caspase-dependent apoptosis via the mitochondrial pathway rather than the death receptor pathway. Considering the possible contributions of BCL-2 and BCL-XL to multidrug resistance, FR901228 is a promising agent in the treatment of refractory as well as primary SCLC tumors.