Horita Henrick, Thorburn Jacqueline, Frankel Arthur E, Thorburn Andrew
Department of Pharmacology, University of Colorado Denver School of Medicine, 12801 E. 17th Ave., Room L18-6100, Aurora, CO, 80045, USA.
Department of Hematology/Oncology, Scott & White Cancer Research Institute, 5701 S. Airport Rd, Temple, TX, 76502, USA.
J Neurooncol. 2009 Nov;95(2):175-184. doi: 10.1007/s11060-009-9914-4. Epub 2009 May 17.
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.
多形性胶质母细胞瘤（GBM）的现有治疗方法包括手术、放疗和细胞毒性化疗；然而，这些治疗方法并不有效，因此迫切需要更好的治疗方法。我们研究了一种新型药物组合对GBM细胞的杀伤作用，该组合包括DT-EGF（一种靶向表皮生长因子受体的细菌毒素）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）或激活TRAIL受体DR4和DR5的抗体。DT-EGF通过非凋亡机制杀死GBM细胞，而TRAIL通过诱导凋亡来杀伤细胞。用DT-EGF和TRAIL处理的GBM细胞在体外以协同方式被杀死，并且该组合在体内比单独的任何一种治疗都更有效。联合治疗导致肿瘤细胞死亡是通过半胱天冬酶激活和凋亡实现的，这是因为DT-EGF通过消耗FLIP（TRAIL受体诱导凋亡的选择性抑制剂）来正向调节TRAIL的杀伤作用。这些数据为联合使用靶向毒素和TRAIL受体激动剂治疗GBM提供了基于机制的理论依据。
