Resistance to TRAIL-induced apoptosis in ovarian cancer cell lines is overcome by co-treatment with cytotoxic drugs.
BACKGROUND
TRAIL, tumor necrosis factor-related apoptosis-inducing ligand, is a recently identified cytokine that preferentially kills transformed cells while sparing most normal cells.


METHODS
We investigated the ability of TRAIL alone and TRAIL in combination with cytotoxic drugs to induce apoptosis in six ovarian cancer cell lines. To get some insight into the resistance to TRAIL, the expression of TRAIL receptors and selected downstream signaling elements was determined.


RESULTS
TRAIL induced significant apoptosis (up to 80%) in three out of six ovarian cancer cell lines (MZ-26, CaOV-3, ES-2). In A2780 and A2780ADR cells, resistance to TRAIL-induced apoptosis correlated with their lack of DR4-expression. MZ-15 cells, which expressed the processed form of FLIP(L), p43 (FADD-like IL-1beta-converting enzyme (FLICE)-like inhibitory protein (FLIP)), and FLIP(S), were resistant to TRAIL in spite of the presence of DR4. When TRAIL-resistant cell lines were co-incubated with routinely used cytotoxic agents, TRAIL exerted a synergistic effect leading to apoptosis rates unachievable by incubation with cytotoxic agents alone.


CONCLUSIONS
The ability of TRAIL to induce apoptosis in ovarian cancer cells as well as to potentiate the activity of chemotherapeutic agents even in cell lines that are resistant to TRAIL-induced cytotoxicity is a powerful promise in the fight against this deadly disease.
Tomek
Sandra
S
Department of Medicine I, University Hospital Vienna, Vienna, Austria.
Horak
Peter
P
Pribill
Ingrid
I
Haller
Griet
G
Rössler
Max
M
Zielinski
Christoph C
CC
Pils
Dietmar
D
Krainer
Michael
M
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D016190:Carboplatin / Q000008:administration & dosage; D002352:Carrier Proteins / Q000096:biosynthesis; D053181:Caspase 8; D020169:Caspases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D053244:Osteoprotegerin; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D019772:Topotecan / Q000008:administration & dosage; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C506030:TNFRSF11B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019772:Topotecan; D004317:Doxorubicin; D016190:Carboplatin; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; D017239:Paclitaxel