High sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide

Alessia Petronelli; Ernestina Saulle; Luca Pasquini; Eleonora Petrucci; Gualtiero Mariani; Mauro Biffoni; Gianluigi Ferretti; Giovanni Scambia; Pierluigi Benedetti-Panici; Stefano Greggi; Francesco Cognetti; Matteo Antonio Russo; Michael Sporn; Ugo Testa

doi:10.1016/j.canlet.2009.03.018

High sensitivity of ovarian cancer cells to the synthetic triterpenoid CDDO-Imidazolide

Cancer Lett. 2009 Sep 18;282(2):214-28. doi: 10.1016/j.canlet.2009.03.018. Epub 2009 Apr 11.

Authors

Alessia Petronelli¹, Ernestina Saulle, Luca Pasquini, Eleonora Petrucci, Gualtiero Mariani, Mauro Biffoni, Gianluigi Ferretti, Giovanni Scambia, Pierluigi Benedetti-Panici, Stefano Greggi, Francesco Cognetti, Matteo Antonio Russo, Michael Sporn, Ugo Testa

Affiliation

¹ Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

PMID: 19364626
DOI: 10.1016/j.canlet.2009.03.018

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

Research Support, Non-U.S. Gov't

MeSH terms

Antibiotics, Antineoplastic / pharmacology*
Apoptosis / drug effects
Caspase 8 / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm
Enzyme Activation / drug effects
Female
Glutathione / metabolism
Humans
Imidazoles / pharmacology*
Mitochondria / drug effects
Oleanolic Acid / analogs & derivatives*
Oleanolic Acid / pharmacology
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / pathology
Receptors, TNF-Related Apoptosis-Inducing Ligand / analysis
Receptors, Tumor Necrosis Factor / analysis
STAT3 Transcription Factor / metabolism
TNF-Related Apoptosis-Inducing Ligand / pharmacology
bcl-2-Associated X Protein / metabolism

Substances

1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
Antibiotics, Antineoplastic
BAX protein, human
Imidazoles
Receptors, TNF-Related Apoptosis-Inducing Ligand
Receptors, Tumor Necrosis Factor
STAT3 Transcription Factor
STAT3 protein, human
TNF-Related Apoptosis-Inducing Ligand
TNFRSF10A protein, human
bcl-2-Associated X Protein
Oleanolic Acid
Caspase 8
Glutathione