Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinoma.
Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinoma.
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DOI：
10.1016/j.jss.2010.03.067
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Vickers SM
中科院分区：
文献类型：
--
作者：
Clawson KA;Borja-Cacho D;Antonoff MB;Saluja AK;Vickers SM
胆管细胞癌起源于肝内外胆管系统的胆管上皮细胞。我们最近观察到雷公藤甲素(一种二萜类三环氧化物)能有效地诱导胰腺肿瘤细胞凋亡。死亡受体4和5在几种癌症中过表达，它们被TRAIL激活后诱导细胞死亡。本研究的主要目的是确定TRAIL和雷公藤甲素联合治疗胆管癌细胞的效果。两种胆管癌细胞系分别与不同剂量的雷公藤甲素和TRAIL单独及联合孵育，分别在24小时和48小时检测细胞活力。在雷公藤甲素、TRAIL或联合用药24小时后，检测细胞膜联蛋白染色和caspase-3活性。Western blotts检测PARP和XIAP的蛋白水平。联合使用TRAIL和雷公藤甲素可降低48小时内所有细胞系的细胞存活率，其细胞杀伤率比单独使用任何一种药物都要大。存活率的下降与Annexin染色和caspase-3活性的增加有关。Western印迹分析显示，PARP裂解增加，XIAP表达减少，且呈剂量依赖性。TRAIL和雷公藤甲素联合应用可降低细胞存活率，促进细胞凋亡。此外，Western印迹分析表明，雷公藤甲素通过抑制XIAP的表达而使细胞对TRAIL诱导的细胞凋亡敏感。XIAP是一种已知的抑制细胞凋亡的蛋白质。我们的结果表明，TRAIL和雷公藤甲素联合应用可促进胆管癌细胞系的凋亡。
Cholangiocarcinoma originates from bile duct epithelial cells in the intrahepatic and extrahepatic biliary system. We recently observed that triptolide (a diterpenoid triepoxide) is effective in inducing apoptosis in pancreatic tumors. Death Receptors 4 and 5 are overexpressed in several cancer types, and their activation by TRAIL induces cell death. The principal objective of this study was to determine the effects of combination therapy with TRAIL and triptolide in cholangiocarcinoma. Two cholangiocarcinoma cell lines were incubated with various doses of triptolide and TRAIL, alone and in combination; cell viability was assessed at 24 and 48 hours. Annexin staining and caspase-3 activity were measured after 24 hours of triptolide, TRAIL or combination treatment. Western blots assessed protein levels of PARP and XIAP. Combination treatment using TRAIL and triptolide decreased cell viability in all cell lines at 48 hours, with greater cell killing than that which was observed with either drug alone. This decrease in viability was associated with increases in Annexin staining and caspase-3 activity. Western blot analysis demonstrated increases in PARP cleavage and decreases in XIAP expression that were dose-dependent. TRAIL and triptolide in combination decreased cell viability and enhanced apoptosis. Furthermore, Western blot analysis suggests that triptolide sensitizes cells to TRAIL-induced apoptotic cell death by inhibiting expression of XIAP, a protein known to inhibit apoptosis. Our results demonstrate that combination of TRAIL and triptolide enhance apoptosis in cholangiocarcinoma cell lines.
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