Abstract
In the present study we have explored the sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide (CDDO-Im). For these studies we have used the A2780 ovarian cancer cell line and its chemoresistant derivatives A2780/ADR and A2780/CISP, OVCAR3, SKOV3 and HEY cancer cell lines and primary ovarian cancer cells, providing evidence that: (i) the majority of these cell lines are highly sensitive to the pro-apoptotic effects induced by CDDO-Im; (ii) TRAIL, added alone exerted only a weak proapoptotic, but clearly potentiated the cytotoxic effect elicited by CDDO-Im; (iii) the apoptotic effect induced by CDDO-Im involves GSH depletion, c-FLIP downmodulation and caspase-8 activation; (iv) CDDO-Im inhibits STAT3 activation and CDDO-Im sensitivity is inversely related to the level of constitutive STAT3 activation. Importantly, studies on primary ovarian cancer cells have shown that these cells are sensitive to the pro-apoptotic effects of CDDO-Im. These observations support the experimental use of synthetic triterpenoids in the treatment of ovarian cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibiotics, Antineoplastic / pharmacology*
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Apoptosis / drug effects
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Caspase 8 / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm
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Enzyme Activation / drug effects
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Female
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Glutathione / metabolism
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Humans
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Imidazoles / pharmacology*
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Mitochondria / drug effects
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Oleanolic Acid / analogs & derivatives*
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Oleanolic Acid / pharmacology
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / pathology
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Receptors, TNF-Related Apoptosis-Inducing Ligand / analysis
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Receptors, Tumor Necrosis Factor / analysis
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STAT3 Transcription Factor / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology
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bcl-2-Associated X Protein / metabolism
Substances
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1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
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Antibiotics, Antineoplastic
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BAX protein, human
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Imidazoles
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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STAT3 Transcription Factor
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STAT3 protein, human
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10A protein, human
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bcl-2-Associated X Protein
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Oleanolic Acid
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Caspase 8
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Glutathione