Synergistic cytotoxic effect of TRAIL and gemcitabine in pancreatic cancer cells.
BACKGROUND
Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a novel member of the TNF family and triggers apoptosis in a variety of malignant cells.


METHODS
We assessed the antitumour activity of TRAIL in six human pancreatic cancer cell lines by measuring apoptosis with sulforhodamine B cytotoxicity assays, DAPI staining and FACScans.


RESULTS
All six cell lines were sensitive to TRAIL-induced apoptosis. The expression levels of TRAIL receptors R1, R2, R3 and R4 did not correlate with TRAIL sensitivity. Simultaneous treatment with TRAIL and the chemotherapeutic agent gemcitabine had a synergistic effect. Caspase-8 and -3 activities were increased by TRAIL treatment and apoptosis was largely blocked by caspase-8 and -3 inhibitors.


CONCLUSIONS
Apoptotic cell death can be induced in pancreatic cancer cells by TRAIL treatment and this may be mediated through activation of caspases-8 and -3. Gemcitabine significantly increased the antitumour effect of TRAIL, suggesting novel therapeutic approaches.
Xu
Zhong-Wei
ZW
Department of Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
Kleeff
Jörg
J
Friess
Helmut
H
Büchler
Markus W
MW
Solioz
Marc
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D000093542:Gemcitabine
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D000093542:Gemcitabine