Enhancement of death receptor 4 mediated apoptosis and cytotoxicity in renal cell carcinoma cells by subtoxic concentrations of doxorubicin
Enhancement of death receptor 4 mediated apoptosis and cytotoxicity in renal cell carcinoma cells by subtoxic concentrations of doxorubicin
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DOI：
10.1016/j.juro.2007.01.018
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发表时间：
2007-05-01
影响因子：
6.6
通讯作者：
Kakehi, Yoshiyuki
中科院分区：
文献类型：
--
作者：
Jin, Xinghua;Wu, Xiu-Xian;Kakehi, Yoshiyuki
目的：TRAIL （tumor necrosis factor-related apoptosis-inducing ligand，肿瘤坏死因子相关凋亡诱导配体）通过参与死亡受体4和5触发多种肿瘤细胞的凋亡。本研究利用人死亡受体4特异性单克隆抗体HGS-ETR1研究了化疗药物对死亡受体4介导的人肾癌细胞凋亡的影响。材料与方法：采用3-（4,5-二甲基噻唑-2-基）-2,5-二苯基溴化四唑法测定细胞毒性。协同作用通过等容积分析进行评估。结果：HGS-ETR1联合5-氟尿嘧啶、长春花碱或吉西他滨治疗ACHN人肾细胞癌细胞株均未克服对这些药物的耐药性。然而，HGS-ETR1联合阿霉素治疗具有协同细胞毒作用。在另一种人类肾细胞癌细胞系Caki-1和5种新鲜衍生的肾细胞癌细胞培养物中也实现了协同作用。HGS-ETR1与阿霉素衍生物表柔比星、吡柔比星或氨柔比星联合也观察到协同效应。HGS-ETR1和阿霉素在细胞毒性方面的协同作用也在细胞凋亡方面实现。阿霉素序贯治疗后HGS-ETR1诱导的细胞毒性明显高于反向治疗或同时治疗(p
Purpose: TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) triggers apoptosis in various tumor cells by engaging death receptors 4 and 5. We investigated the effect of chemotherapeutic agents on death receptor 4 mediated apoptosis in human renal cell carcinoma cells using HGS-ETR1, which is a human monoclonal agonistic antibody specific for death receptor 4.Materials and Methods: Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Synergy was assessed by isobolographic analysis.Results: Treatment of the ACHN human renal cell carcinoma cell line with HGS-ETR1 combined with 5-fluorouracil, vinblastine or gemcitabine did not overcome resistance to these agents. However, treatment with HGS-ETR1 combined with doxorubicin had a synergistic cytotoxic effect. Synergy was also achieved in another human renal cell carcinoma cell line, Caki-1, and in 5 freshly derived renal cell carcinoma cell cultures. A synergistic effect was also observed with HGS-ETR1 combined with the doxorubicin derivatives epirubicin, pirarubicin or amrubicin. The synergy achieved in cytotoxicity with HGS-ETR1 and doxorubicin was also achieved in apoptosis. Sequential treatment with doxorubicin followed by HGS-ETR1 induced significantly more cytotoxicity than reverse treatment or simultaneous treatment (p