Sensitization of resistant lymphoma cells to irradiation-induced apoptosis by the death ligand TRAIL.
A combination of antitumor approaches acting on different death pathways seems ideal for increasing therapeutic responses, especially when defined resistance mechanisms interfere with individual cellular processes. Apoptosis pathways triggered by ionizing radiation (XRT) and the death ligand TRAIL were analysed in Jurkat lymphoma cells. Both induced the activation of caspase-8, caspase-3, BID and mitochondrial potential loss. TRAIL induced apoptosis required caspase-8, whereas it was not essential for radiation induced apoptosis. The inhibition of mitochondrial damage by Bcl-2 abrogated XRT induced apoptosis and caspase activation, but only marginally attenuated TRAIL induced cell death. The combined treatment with TRAIL and XRT exerted additive apoptotic effects in control cells, whereas highly synergistic effects occurred in cells overexpressing Bcl-2. In addition, a strong effect of TRAIL on radiation induced clonogenic cell death was found. In conclusion, TRAIL seems to be of high potential value for a combination with ionizing radiation in tumor therapy.
Belka
C
C
Department of Radiation Oncology, University of Tübingen (Germany), Hoppe-Seyler Str. 3, D-72076 Tübingen, Germany.
Schmid
B
B
Marini
P
P
Durand
E
E
Rudner
J
J
Faltin
H
H
Bamberg
M
M
Schulze-Osthoff
K
K
Budach
W
W
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects*; D051017:Apoptosis Regulatory Proteins; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D008562:Membrane Glycoproteins; D011838:Radiation-Sensitizing Agents; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases