APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo
APO010, a synthetic hexameric CD95 ligand, induces human glioma cell death in vitro and in vivo
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DOI：
10.1093/neuonc/noq176
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发表时间：
2011-02-01
期刊：
影响因子：
15.9
通讯作者：
Weller, Michael
中科院分区：
文献类型：
--
作者：
Eisele, Guenter;Roth, Patrick;Weller, Michael
死亡受体靶向治疗已成为肿瘤治疗的一种有前途的新方法。一种这样的原型死亡受体CD 95（Fas/APO-1）的激活仍然存在争议，因为CD 95激动性分子表现出太强的毒性或太小的活性。天然的CD 95配体（CD 95 L）是一种细胞因子，其需要三聚化以介导细胞死亡信号。Mega-Fas-Ligand，现称为APO 010，是一种合成的六聚体CD 95激动剂，在各种肿瘤模型中表现出强烈的抗肿瘤活性。本研究在体外和体内研究了APO 010在人脑胶质瘤模型中的作用。与交联的可溶性CD 95 L或CD 95激动性抗体相比，APO 010在表达CD 95的胶质瘤细胞系中表现出上级活性，并触发半胱天冬酶依赖性细胞死亡。当与替莫唑胺组合时，APO 010协同降低胶质瘤细胞活力。APO 010的局部给药在体内诱导胶质瘤细胞死亡，并延长荷瘤小鼠的生存期。有必要进一步探索APO 010作为一种新型抗胶质瘤药物。
Death receptor targeting has emerged as one of the promising novel approaches of cancer therapy. The activation of one such prototypic death receptor, CD95 (Fas/APO-1), has remained controversial because CD95 agonistic molecules have exhibited either too strong toxicity or too little activity. The natural CD95 ligand (CD95L) is a cytokine, which needs to trimerize to mediate a cell death signal. Mega-Fas-Ligand, now referred to as APO010, is a synthetic hexameric CD95 agonist that exhibits strong antitumor activity in various tumor models. Here, we studied the effects of APO010 in human glioma models in vitro and in vivo. Compared with a cross-linked soluble CD95L or a CD95-agonistic antibody, APO010 exhibited superior activity in glioma cell lines expressing CD95 and triggered caspase-dependent cell death. APO010 reduced glioma cell viability in synergy when combined with temozolomidc. The locoregional administration of APO010 induced glioma cell death in vivo and prolonged the survival of tumor-bearing mice. A further exploration of APO010 as a novel antiglioma agent is warranted.