TRAIL-induced cytotoxicity in a melphalan-resistant rhabdomyosarcoma cell line via activation of caspase-2.
The prognosis for patients with chemo-refractory rhabdomyosarcoma remains poor. The tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a hopeful candidate for new strategies in chemotherapy. The effects of TRAIL and melphalan (Mel) in the rhabdomyosarcoma cell line TE-671 were investigated by colorimetric caspase assays and flow cytometry. TRAIL induced the activation of caspases-2, -3 and -8, but not the activation of caspase-9, in the Mel-resistant TE-671 cells. Inhibition of caspase-2 with the caspase-2 inhibitor z-VDVAD-fmk significantly down-regulated the TRAIL-induced caspase-3 activation, as well as the TRAIL-induced cytotoxicity. When TE-671 cells were treated with a combination of Mel and TRAIL, a significant synergism of drug-induced cytotoxicity was obtained. The inhibition of caspase-2 could completely abolish caspase-3 activation, suggesting that TRAIL sensitises TE-671 cells for Mel-induced cytotoxicity via a caspase-2- and -3-dependent mechanism. In conclusion, it was shown, for the first time, that TRAIL could sensitise Mel-resistant tumour cells to melphalan.
Division of Paediatric Haematology and Oncology, Department of Paediatrics, University of Leipzig, Germany.
K
K
Klüttermann
U
U
Banning
M
M
Kachel
C
C
Krause
D
D
Körholz
C
C
Mauz-Körholz
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D053143:Caspase 2; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D053143:Caspase 2; D020169:Caspases; D008558:Melphalan