Matsuzaki H, Schmied B M, Ulrich A, Standop J, Schneider M B, Batra S K, Picha K S, Pour P M
UNMC Eppley Cancer Center, University of Nebraska Medical Center, Omaha 68198-6805, USA.
Clin Cancer Res. 2001 Feb;7(2):407-14.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a novel member of the tumor necrosis factor superfamily of cytokines that induces cell death by apoptosis. TRAIL has been shown to be effective in almost two-thirds of solid tumors tested thus far, but its effect on pancreatic cancer cells is unknown. We tested the effect of TRAIL on seven human pancreatic cancer cell lines (HPAF, Panc1, Miapaca2, Bxpc3, Panc89, SW979, and Aspc1) in vitro. Of these cell lines, all but Aspc1 showed a significant dose-dependent increase in apoptosis. The apoptotic rate, as detected by a terminal deoxynucleotidyl transferase-mediated nick end labeling assay, was highest in Bxpc3 (71.5%), followed by HPAF (38.0%), Miapaca2 (24.9%), Panc1 (16.1%), Panc89 (15.8%), SW979 (13.9%), and Aspc1 (5.2%). Multiple treatments were more effective than a single treatment and caused a sustained and profound cell death in all but Aspc1 cells. There was no correlation between the effect of TRAIL and the differentiation grade of the cell lines, p53 mutation, or bcl-2 or bax expression. The resistance of Aspc1 cells to TRAIL was not related to the lack of TRAIL receptors. The combination of actinomycin D and TRAIL induced an almost complete lysis of Aspc1 cells, whereas actinomycin D alone had no effect on cell survival but inhibited the expression of the Flice inhibitory protein, which is assumed to play a role in the apoptotic pathway of TRAIL. Thus, the combination of actinomycin D and TRAIL appears to be a promising approach for the therapy of pancreatic cancers resistant to TRAIL.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是肿瘤坏死因子超家族细胞因子中的一个新成员，它通过凋亡诱导细胞死亡。到目前为止，TRAIL已被证明在近三分之二的测试实体瘤中有效，但其对胰腺癌细胞的作用尚不清楚。我们在体外测试了TRAIL对七种人胰腺癌细胞系（HPAF、Panc1、Miapaca2、Bxpc3、Panc89、SW979和Aspc1）的影响。在这些细胞系中，除了Aspc1之外，其他所有细胞系均显示出凋亡呈显著的剂量依赖性增加。通过末端脱氧核苷酸转移酶介导的缺口末端标记试验检测到的凋亡率，在Bxpc3中最高（71.5%），其次是HPAF（38.0%）、Miapaca2（24.9%）、Panc1（16.1%）、Panc89（15.8%）、SW979（13.9%）和Aspc1（5.2%）。多次治疗比单次治疗更有效，并且除了Aspc1细胞之外，在所有细胞系中都导致了持续且显著的细胞死亡。TRAIL的作用与细胞系的分化程度、p53突变或bcl-2或bax表达之间没有相关性。Aspc1细胞对TRAIL的抗性与缺乏TRAIL受体无关。放线菌素D和TRAIL的联合使用诱导了Aspc1细胞几乎完全裂解，而单独使用放线菌素D对细胞存活没有影响，但抑制了假定在TRAIL凋亡途径中起作用的Flice抑制蛋白的表达。因此，放线菌素D和TRAIL的联合使用似乎是治疗对TRAIL耐药的胰腺癌的一种有前景的方法。
