Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo
Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo
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DOI：
10.1038/nm735
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发表时间：
2002-08-01
期刊：
影响因子：
82.9
通讯作者：
Debatin, KM
中科院分区：
文献类型：
--
作者：
Fulda, S;Wick, W;Debatin, KM
癌症治疗的一个主要问题是胶质母细胞瘤等肿瘤对当前治疗方案的耐药性。在这里，我们报道了编码第二线粒体来源的半胱天冬酶激活因子（Smac）或Smac肽的基因的转移，使体外的各种肿瘤细胞和体内的恶性胶质瘤细胞对死亡受体连接或细胞毒性药物诱导的凋亡敏感。胞浆内活性形式的Smac或细胞渗透性Smac肽的表达绕过Bcl-2阻滞，从而阻止Smac从线粒体释放，并且还使耐药神经母细胞瘤或黑色素瘤细胞和患者源性原发性神经母细胞瘤细胞致敏。最重要的是，Smac肽在体内强烈增强了Apo2L/肿瘤坏死因子相关凋亡诱导配体（TRAIL）在颅内恶性胶质瘤异种移植模型中的抗肿瘤活性。只有在Smac肽和Apo2L/TRAIL的联合治疗下，小鼠才能完全根除已建立的肿瘤并存活下来，而对正常脑组织没有可检测到的毒性。因此，Smac激动剂是通过增强细胞毒性治疗来治疗癌症的有希望的候选者。
A major concern in cancer therapy is resistance of tumors such as glioblastoma to current treatment protocols. Here, we report that transfer of the gene encoding second mitochondria-derived activator of caspase ( Smac) or Smac peptides sensitized various tumor cells in vitro and malignant glioma cells in vivo for apoptosis induced by death-receptor ligation or cytotoxic drugs. Expression of a cytosolic active form of Smac or cell-permeable Smac peptides bypassed the Bcl-2 block, which prevented the release of Smac from mitochondria, and also sensitized resistant neuroblastoma or melanoma cells and patient-derived primary neuroblastoma cells ex vivo. Most importantly, Smac peptides strongly enhanced the antitumor activity of Apo2L/tumor necrosis factor - related apoptosis-inducing ligand ( TRAIL) in an intracranial malignant glioma xenograft model in vivo. Complete eradication of established tumors and survival of mice was only achieved upon combined treatment with Smac peptides and Apo2L/TRAIL without detectable toxicity to normal brain tissue. Thus, Smac agonists are promising candidates for cancer therapy by potentiating cytotoxic therapies.