EGFR-targeted diphtheria toxin stimulates TRAIL killing of glioblastoma cells by depleting anti-apoptotic proteins.
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.
Horita
Henrick
H
Department of Pharmacology, University of Colorado Denver School of Medicine, 12801 E. 17th Ave., Room L18-6100, Aurora, CO, 80045, USA.
Thorburn
Jacqueline
J
Department of Pharmacology, University of Colorado Denver School of Medicine, 12801 E. 17th Ave., Room L18-6100, Aurora, CO, 80045, USA.
Frankel
Arthur E
AE
Department of Hematology/Oncology, Scott & White Cancer Research Institute, 5701 S. Airport Rd, Temple, TX, 76502, USA.
Thorburn
Andrew
A
Department of Pharmacology, University of Colorado Denver School of Medicine, 12801 E. 17th Ave., Room L18-6100, Aurora, CO, 80045, USA. Andrew.Thorburn@ucdenver.edu.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000473:pathology*; D020169:Caspases / Q000378:metabolism; D004167:Diphtheria Toxin / Q000235:genetics; D004357:Drug Synergism; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D004167:Diphtheria Toxin; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D066246:ErbB Receptors; D020169:Caspases