Time sequence of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cisplatin treatment is responsible for a complex pattern of synergistic cytotoxicity
Time sequence of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cisplatin treatment is responsible for a complex pattern of synergistic cytotoxicity
复制标题
DOI：
10.1002/jcb.20844
复制
发表时间：
2006-08-01
影响因子：
4
通讯作者：
Lee, Yong J.
中科院分区：
文献类型：
--
作者：
Kim, Young-Ho;Lee, Yong J.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）和顺铂的组合导致了更大的细胞毒性比可以通过单独添加剂的细胞毒性作用占。在这项研究中，我们假设，当两种治疗之间的顺序和时间间隔都不同时，两种方式之间的协同作用可以改变。为了检验该假设，人头颈部鳞状细胞癌（HNSCC）-6细胞用0.01 - 0.5 μ g/ml TRAIL预处理不同时间（0-24小时），然后用5 μ g/ml顺铂处理，或用5 μ g/ml顺铂预处理不同时间（0-24小时），然后用0.5 μ g/ml TRAIL处理。在后一种情况下，随着两种处理之间的时间间隔的增加，协同效应逐渐增加。在前一种情况下，最大协同作用发生在用TRAIL预处理的0-4 h内。但随着处理间隔时间的延长，协同效应逐渐减弱。来自免疫印迹分析的数据显示，PARP切割和半胱天冬酶活化出现了类似的模式。协同效应与DR 4、DR 5、FADD和FLIPL无关。有趣的是，TRAIL和顺铂之间的协同相互作用的复杂模式与FLIPS的切割有关。尽管FLIPS的过表达保护细胞免于FLIPS切割和凋亡性死亡，但是通过用丙氨酸替换ASP（39）和Asp（42）残基来阻断FLIPS切割并没有进一步增强FLIPS介导的保护。总之，FLIPS切割反映了凋亡损伤，但它不引起凋亡。
The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cisplatin resulted in a greater cytotoxicity than could be accounted for by the addition of the cytotoxic effects of the agents alone. In this study, we hypothesized that the synergistic interaction between the two modalities can be changed when both the sequence and the time interval between the two treatments are varied. To test the hypothesis, human head-and-neck squamous-cell carcinoma (HNSCC)-6 cells were either pretreated with 0.01 - 0.5 mu g/ml TRAIL for various times (0-24 h) followed by treatment with 5 mu g/ml cisplatin or pretreated with 5 mu g/ml cisplatin for various times (0-24 h) followed by treatment with 0.5 pg/ml TRAIL. In latter case, the synergistic effect was gradually increased when the time interval between the two treatments was increased. In former case, a maximal synergy occurred within 0-4 h of pretreatment with TRAIL. However, the synergistic effect was gradually decreased when the time interval between the two treatments was increased. Data from immunoblotting analysis reveal that a similar pattern emerged for the PARP cleavage and caspase activation. The synergistic effect is not associated with DR4, DR5, FADD, and FLIPL. Interestingly, a complex pattern of synergistic interaction between TRAIL and cisplatin is related to the cleavage of FLIPS. Although overexpression of FLIPS protected cells from FLIPS cleavage and apoptotic death, blockage of FLIPS cleavage by replacing ASP(39) and Asp(42) residues with alanine did not further enhance FLIPS-mediated protection. Taken together, FLIPS cleavage reflects apoptotic damage, but it does not cause apoptosis.