Physiological and molecular effects of Apo2L/TRAIL and cisplatin in ovarian carcinoma cell lines.
Combining of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) with a chemotherapeutic drug, cisplatin, in ovarian carcinoma cell lines exerted potent anti-tumor effects that exceeded the effects of each drug alone. In order to investigate mechanisms of anti-tumor activity of cisplatin/Apo2L/TRAIL combination, we assessed in detail the molecular effects of cisplatin and Apo2L/TRAIL-activated cell death in two ovarian carcinoma cell lines, OVCAR3 and SKOV3, using cDNA array hybridization, Western blot and flow cytometry. We observed differential induction of apoptosis-related molecules by cisplatin and Apo2L/TRAIL. Cisplatin upregulated the expression of both death and decoy TRAIL receptors, as well as of TRAF5 and -6, downregulated the anti-apoptotic proteins, Bcl-2, and induced activation of caspases-3, -8 and -9. Apo2L/TRAIL induced the expression of pro-apoptotic proteins, Bad and Bax; downregulated the anti-apoptotic proteins, Bcl-2 and Bcl-xL; and activated caspases-3, -7, -8, -9 and -10. Cisplatin/Apo2L/TRAIL combination resulted in further downregulation of expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL, as well as an increase in mitochondrial permeability transition and activation of caspases-3, -8, and -10. These data demonstrate positive cooperation of cisplatin and Apo2L/TRAIL and emphasize the potential clinical usefulness of cisplatin/Apo2L/TRAIL combination therapy.
Siervo-Sassi
R R
RR
Department of Ob/Gyn Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, 204 Craft Avenue, Pittsburgh, PA 15213, USA.
Marrangoni
A M
AM
Feng
X
X
Naoumova
N
N
Winans
M
M
Edwards
R P
RP
Lokshin
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002455:Cell Division; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology*; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation; D051020:bcl-X Protein
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494811:BCL2L1 protein, human; D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D020169:Caspases; D002945:Cisplatin