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顺铂以caspase依赖方式加强人类实体瘤细胞中来沙木单抗诱导的凋亡

Enhancement of lexatumumab-induced apoptosis in human solid cancer cells by cisplatin in caspase-dependent manner
Wu X.-X., Kakehi Y.   |   2009/5/29 18:40:37 
Clinical Cancer Research, 2009   |   Volume 15, Issue 6  |   打印| 推荐给好友
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Purpose: This study was designed to evaluate the apoptotic effect of mapatumumab or lexatumumab, human agonistic antibodies that target the tumor necrosis factor related apoptosisinducing ligand receptor 1 (TRAIL-R1) and receptor 2 (TRAIL-R2), in combination with chemotherapeutic agents, against human solid cancer cells. Experimental Design: Cytotoxicity was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5diphenyltetrazolium bromide assay. Synergy was assessed by isobolographic analysis. Results: Treatment of ACHN human renal cell carcinoma cells with cisplatin combined with mapatumumab did not overcome resistance to these agents. However, treatment with cisplatin in combination with lexatumumab had a synergistic cytotoxicity. Synergy was also achieved in sixprimary renal cell carcinoma cell cultures. Lexatumumab and cisplatin also synergistically enhanced apoptosis. Pretreatment with cisplatin followed by lexatumumab resulted in high cytotoxicity compared with the reverse sequence. Cisplatin significantly increased TRAIL-R2 expression at both the mRNA and the protein levels. Furthermore, the combination of lexatumumab and cisplatin significantly enhanced caspase-8 activity, Bid cleavage, up-regulation of Bax, cytochrome c release, and caspase-9, caspase-6, and caspase-3 activities. Importantly, the activation of caspase-8 was significantly abrogated by the specific inhibitors of caspase-9, caspase-6, and caspase-3. Furthermore, combination-induced cytotoxicity was significantly suppressed by the DR5:Fc chimeric protein and the specific inhibitors of caspase-8, caspase-9, caspase-6, and caspase-3. A similar effect was observed in prostate cancer, bladder cancer, lung cancer, and cervical cancer cells. Conclusions: Cisplatin sensitizes solid cancer cells to lexatumumab-induced apoptosis by potentiation of the extrinsic and intrinsic apoptotic pathways that lead to amplification of caspase activation, particularly caspase-8, suggesting the combination treatment of solid cancers with cisplatin and lexatumumab might overcome their resistance. © 2009 American Association for Cancer Research.
Correspondence Address: Wu, X.-X.; Department of Urology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; email: wuxian@med.kagawa-u.ac.jp 
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慢性心衰诊治：规范中求突破
黄峻
2012-2-1
南京医科大学第一附属医院
房颤治疗：手段渐趋丰富 新型治疗药物不断涌现 非药物治疗备受关注
马长生
2012-2-1
首都医科大学附属北京安贞医院
注重老年人群特征 优化管理

刘梅林
2012-2-1
北京大学第一医院老年内科

 
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