In vitro effects of topotecan and ionizing radiation on TRAIL/Apo2L-mediated apoptosis in malignant glioma
In vitro effects of topotecan and ionizing radiation on TRAIL/Apo2L-mediated apoptosis in malignant glioma
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DOI：
10.1007/s11060-004-9180-4
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发表时间：
2005-01-01
影响因子：
3.9
通讯作者：
Salmaggi, A
中科院分区：
文献类型：
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作者：
Ciusani, E;Croci, D;Salmaggi, A
恶性胶质瘤患者的生存率仍然不令人满意，尽管综合治疗，因此需要新的治疗策略。肿瘤坏死因子凋亡相关配体（tumor necrosis factor apoptosis related ligand，TRAIL/Apo 2L）是肿瘤坏死因子超家族成员之一，与特异性受体结合后可诱导多种肿瘤细胞凋亡，但在正常细胞中不诱导凋亡。在本研究中，TRAIL受体（TRAIL-R1/DR 4和TRAIL-R2/DR 5）的表达和功能已在五个人胶质瘤细胞系（U87，U138，U373，A172，SW 1783）在离体肿瘤和从肿瘤获得的原代培养物中进行了研究。我们的数据表明，胶质瘤优先表达TRAIL R2和拓扑替康，拓扑异构酶I抑制剂，治疗显着上调其表达，通过流式细胞术和蛋白质印迹检测。此外，在大多数情况下，拓扑替康治疗导致TRAIL依赖性细胞凋亡的敏感性增加，尽管必须加入环己酰亚胺来诱导细胞凋亡。在胶质瘤细胞系上，还分析了辐射对TRAIL受体的影响。在我们的实验条件下，用2戈伊照射对TRAIL依赖性细胞凋亡有适度的累加效应，并且不能调节TRAIL受体的表达。
The survival of patients with malignant gliomas is still unsatisfactory despite multimodality treatment, therefore new therapeutic strategies are required. Tumor necrosis factor apoptosis related ligand (TRAIL/Apo2L), a member of the tumor necrosis factor superfamily, may induce apoptotic cell death in several tumors, but not in normal cells, upon binding with specific receptors. In the present study, the expression and function of TRAIL receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5) has been investigated in five human glioma cell lines (U87, U138, U373, A172, SW1783) in ex vivo tumors and in primary cultures obtained from the tumors. Our data show that gliomas preferentially express TRAIL R2 and that treatment with topotecan, a topolsomerase I inhibitor, significantly up-regulates its expression as detected by flow cytometry and western blotting. Moreover, in most cases, treatment with topotecan resulted in an increased sensitivity to TRAIL-dependent apoptosis, although cyclohexymide had to be added to induce apoptosis. On glioma cell lines, the effects of irradiation on TRAIL receptors were also analysed. In our experimental conditions, irradiation with 2 Gy had a modest additive effect on TRAIL-dependent apoptosis and was not able to modulate TRAIL receptor expression.