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Although ovarian tumours initially respond to chemotherapy, they gradually acquire drug resistance. The aims of this study were to identify how chemotherapeutic drugs with diverse cellular targets activate apoptotic pathways and to investigate the mechanism by which exposure to a combination of drugs plus death receptor ligands can increase tumour cell kill. The results show that drugs with distinct cellular targets differentially up-regulate TRAIL and TNF as well CD95L, but do not require interaction of these ligands with their receptor partners to induce cell death. Factors that were critical in drug-induced apoptosis were activation of caspases, with caspase-8 being activated by diverse drugs in a FADD-independent manner. Certain drugs also demonstrated some dependence on FADD in the induction of cell death. Caspase-9 was activated more selectively by chemotherapeutic agents. Combining ligation of death receptors with exposure to drugs increased tumour cell kill in both drug resistant cell lines and primary ovarian carcinoma cells, even though these cells were not sensitive to death receptor ligation alone. CD95L was more consistent at combining with drugs than TRAIL or TNF. Investigation of the mechanism by which a combination of drugs plus CD95 ligation can increase cell death showed that caspase-8 was activated in cells exposed to a combination of cisplatin and anti-CD95, but not in cells exposed to either agent alone.

Original publication

DOI

10.1038/sj.cdd.4400945

Type

Journal article

Journal

Cell Death Differ

Publication Date

03/2002

Volume

9

Pages

287 - 300

Keywords

Adaptor Proteins, Signal Transducing, Adenoviridae, Antineoplastic Agents, Apoptosis, Apoptosis Regulatory Proteins, Carrier Proteins, Caspase 3, Caspase 8, Caspase 9, Caspases, Cisplatin, Drug Combinations, Drug Resistance, Neoplasm, Drug Synergism, Enzyme Activation, Fas Ligand Protein, Fas-Associated Death Domain Protein, Female, Humans, Membrane Glycoproteins, Ovarian Neoplasms, TNF-Related Apoptosis-Inducing Ligand, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha, Up-Regulation