EGFR-targeted diphtheria toxin stimulates TRAIL killing of glioblastoma cells by depleting anti-apoptotic proteins.
EGFR-targeted diphtheria toxin stimulates TRAIL killing of glioblastoma cells by depleting anti-apoptotic proteins.
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DOI：
10.1007/s11060-009-9914-4
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发表时间：
2009-11
影响因子：
3.9
通讯作者：
Thorburn A
中科院分区：
文献类型：
--
作者：
Horita H;Thorburn J;Frankel AE;Thorburn A
目前对多形性胶质母细胞瘤（GBM）的治疗包括手术、放疗和细胞毒性化疗;然而，这些治疗并不有效，迫切需要更好的治疗。我们研究了一种新型药物组合对GBM细胞的杀伤作用，该药物组合涉及DT-EGF（一种表皮生长因子受体靶向细菌毒素）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）或激活TRAIL受体DR 4和DR 5的抗体。DT-EGF通过非凋亡机制杀死GBM细胞，而TRAIL通过诱导凋亡杀死GBM细胞。用DT-EGF和TRAIL处理的GBM细胞在体外以协同方式被杀死，并且组合比体内单独处理更有效。由于DT-EGF通过耗尽FLIP（一种TRAIL受体诱导的细胞凋亡的选择性抑制剂）正调节TRAIL杀伤，通过半胱天冬酶激活和细胞凋亡发生组合的肿瘤细胞死亡。这些数据为靶向毒素和TRAIL受体激动剂联合治疗GBM提供了基于机制的基本原理。
Current treatments for Glioblastoma multiforme (GBM) involve surgery, radiotherapy, and cytotoxic chemotherapy; however, these treatments are not effective and there is an urgent need for better treatments. We investigated GBM cell killing by a novel drug combination involving DT-EGF, an Epidermal Growth Factor Receptor-targeted bacterial toxin, and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) or antibodies that activate the TRAIL receptors DR4 and DR5. DT-EGF kills GBM cells by a non apoptotic mechanism whereas TRAIL kills by inducing apoptosis. GBM cells treated with DT-EGF and TRAIL were killed in a synergistic fashion in vitro and the combination was more effective than either treatment alone in vivo. Tumor cell death with the combination occurred by caspase activation and apoptosis due to DT-EGF positively regulating TRAIL killing by depleting FLIP, a selective inhibitor of TRAIL receptor-induced apoptosis. These data provide a mechanism-based rationale for combining targeted toxins and TRAIL receptor agonists to treat GBM.
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影响因子：
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通讯作者：
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