High sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide.
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.
Petronelli
Alessia
A
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Saulle
Ernestina
E
Pasquini
Luca
L
Petrucci
Eleonora
E
Mariani
Gualtiero
G
Biffoni
Mauro
M
Ferretti
Gianluigi
G
Scambia
Giovanni
G
Benedetti-Panici
Pierluigi
P
Greggi
Stefano
S
Cognetti
Francesco
F
Russo
Matteo Antonio
MA
Sporn
Michael
M
Testa
Ugo
U
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000032:analysis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D000903:Antibiotics, Antineoplastic; C494826:BAX protein, human; D007093:Imidazoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D051028:bcl-2-Associated X Protein; D009828:Oleanolic Acid; D053181:Caspase 8; D005978:Glutathione