Kondo S, Barna B P, Morimura T, Takeuchi J, Yuan J, Akbasak A, Barnett G H
Department of Neurosurgery, Cleveland Clinic Foundation, Ohio 44195, USA.
Cancer Res. 1995 Dec 15;55(24):6166-71.
Increasing the susceptibility of tumor cells to apoptotic cell death following chemotherapy is of importance to the outcome of cancer treatment. Although the tumor suppressor gene p53 is required for efficient induction of apoptosis by chemotherapeutic agents, it is not the only apoptosis mediator gene. The molecular mechanisms mediating apoptosis following chemotherapy via p53-dependent or p53-independent pathways remain unclear. We show here that cis-diamminedichloroplatinum (cisplatin) induces the expression of interleukin-1 beta-converting enzyme (ICE), a mammalian homologue of the Caenorhabditis elegans cell death gene ced-3, in murine and human malignant glioma cells during apoptosis regardless of their p53 status. Furthermore, overexpression of the murine ICE gene induces apoptosis in these tumor cells. The apoptosis induced by cisplatin treatment or murine ICE overexpression can be suppressed by the tetrapeptide ICE inhibitor Ac-YVAD-CMK or the apoptosis inhibitors bcl-2 or bcl-2-related bcl-XL gene. These findings suggest that ICE may mediate apoptosis induced by chemotherapy, and its induction could represent a novel approach for the effective treatment of malignant glioma.
提高肿瘤细胞在化疗后对凋亡性细胞死亡的敏感性对癌症治疗的结果至关重要。尽管肿瘤抑制基因p53是化疗药物有效诱导凋亡所必需的，但它不是唯一的凋亡介导基因。通过p53依赖性或p53非依赖性途径介导化疗后凋亡的分子机制仍不清楚。我们在此表明，顺式二氨二氯铂（顺铂）在凋亡过程中可诱导白细胞介素-1β转换酶（ICE）的表达，ICE是秀丽隐杆线虫细胞死亡基因ced-3的哺乳动物同源物，在鼠类和人类恶性胶质瘤细胞中，无论其p53状态如何均可诱导。此外，鼠类ICE基因的过表达可诱导这些肿瘤细胞凋亡。顺铂治疗或鼠类ICE过表达诱导的凋亡可被四肽ICE抑制剂Ac-YVAD-CMK或凋亡抑制剂bcl-2或bcl-2相关的bcl-XL基因所抑制。这些发现表明，ICE可能介导化疗诱导的凋亡，其诱导可能代表一种有效治疗恶性胶质瘤的新方法。
