Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio
Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio
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DOI：
10.1016/j.canlet.2004.07.045
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发表时间：
2005-01-10
期刊：
影响因子：
9.7
通讯作者：
Kuo, MYP
中科院分区：
文献类型：
--
作者：
Kok, SH;Cheng, SJ;Kuo, MYP
去甲斑泻素是去甲基化的斑泻素类似物，自1984年以来一直在中国用于治疗人类癌症。最近发现它能够通过一种难以捉摸的机制诱导人结肠癌、肝癌和胶质母细胞瘤细胞的凋亡。在这项研究中，我们证明了NCTD还诱导人口腔癌细胞系SAS(p53野生型)和Ca9-22(p53突变型)的凋亡，这一点可以通过核固缩、TUNEL标记、DNA断裂和PARP切割来证明。NCTD诱导的细胞凋亡具有剂量和时间依赖性。我们发现NCTD不诱导Fas和FasL，这意味着它激活了其他的凋亡途径。我们的数据显示，NCTD导致胞浆细胞色素c积聚和caspase-9激活，表明细胞凋亡是通过线粒体介导的途径发生的。NCTD促进了SAS细胞Bax的表达，与其P53状态一致。此外，我们还发现，脑瘫汤可下调SAS大鼠Ca9-22和BCI-X-L中Bcl一2的表达。我们的结果提示，NCTD诱导口腔癌细胞的凋亡可能是通过增加促凋亡/抗凋亡蛋白的比例来实现的。由于P53突变或BCI-XL水平升高的口腔癌细胞对多种化疗药物表现出耐药性，NCTD可能会克服这些细胞的化疗耐药性，为治疗提供潜在的新途径。(C)2004爱思唯尔爱尔兰有限公司。保留所有权利。
Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism. In this study, we demonstrated that NCTD also induces apoptosis in human oral cancer cell lines SAS (p53 wild-type phenotype) and Ca9-22 (p53 mutant) as evidenced by nuclear condensation, TUNEL labeling, DNA fragmentation and cleavage of PARP. Apoptosis induced by NCTD was both dose- and time-dependent. We found NCTD did not induce Fas and FasL, implying that it activated other apoptosis pathways. Our data showed that NCTD caused accumulation of cytosolic cytochrome c and activation of caspase-9, suggesting that apoptosis occurred via the mitochondria mediated pathway. NCTD enhanced the expression of Bax in SAS cells consistent with their p53 status. Moreover, we showed that NCTD downregulated the expression of Bcl-2 in Ca9-22 and BCI-X-L in SAS. Our results suggest that NCTD-induced apoptosis in oral cancer cells may be mediated by an increase in the ratios of proapoptotic to antiapoptotic proteins. Since oral cancer cells with mutant p53 or elevated BCI-XL levels showed resistance to multiple chemotherapeutic agents, NCTD may overcome the chemoresistance of these cells and provide potential new avenues for treatment. (C) 2004 Elsevier Ireland Ltd. All rights reserved.