Trail-induced apoptosis and interaction with cytotoxic agents in soft tissue sarcoma cell lines.
Five human soft tissue sarcoma (STS) cell lines (HTB-82 rhabdomyosarcoma, HTB-91 fibrosarcoma, HTB-92 liposarcoma, HTB-93 synovial sarcoma and HTB-94 chondrosarcoma) were analysed for their sensitivity to tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and the function of the TRAIL apoptotic pathway in these cells. TRAIL induced significant apoptosis (>90%) in HTB-92 and HTB-93 cells, whereas no effect was observed in HTB-82, HTB-91 and HTB-94 cells. TRAIL-Receptor 1 (TRAIL-R1) was expressed in TRAIL-sensitive HTB-92 and HTB-93 cell lines, but not in TRAIL-resistant HTB-91 and HTB-94 cells. HTB-82 cells, which expressed the long (c-FLIP(L)) and short (c-FLIP(S)) splice variants of the FLICE-like inhibitory protein (FLIP), were resistant to TRAIL in spite of the presence of TRAIL-R1. TRAIL-R2,-R3,-R4 and osteoprotegerin (OPG) expression did not correlate with TRAIL sensitivity. Coincubation of TRAIL and doxorubicin led to the overexpression of TRAIL-R2 resulting in a synergistic effect of doxorubicin and TRAIL in TRAIL-sensitive cell lines and in the overcoming of TRAIL-resistance in all of the TRAIL-resistant cell lines, except HTB-91, which lacked caspase 8 expression. These data suggest that TRAIL, either as a single agent or in combination with cytotoxic agents, might represent a new treatment option for advanced STS, which constitutes a largely chemotherapy-resistant disease.
Tomek
S
S
Clinical Division of Oncology, Department of Medicine I, Waehringer Guertel 18-20, A-1090, Vienna, Austria. sandra.tomek@akh-wein.ac.at
Koestler
W
W
Horak
P
P
Grunt
T
T
Brodowicz
T
T
Pribill
I
I
Halaschek
J
J
Haller
G
G
Wiltschke
C
C
Zielinski
C C
CC
Krainer
M
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D017239:Paclitaxel / Q000008:administration & dosage; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D012983:Soft Tissue Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D017239:Paclitaxel