Growth-inhibitory effect of a novel synthetic triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, on ovarian carcinoma cell lines not dependent on peroxisome proliferator-activated receptor-gamma expression.
OBJECTIVE
Despite the advent of new chemotherapeutic drugs in recent decades, epithelial ovarian carcinoma (EOC) remains the leading cause of death from gynecologic cancers, and new therapeutic targets and agents are urgently needed. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a novel synthetic triterpenoid with anti-tumor activity against a wide range of tumors in vitro and in vivo. CDDO is a ligand for the peroxisome proliferator-activated receptor-gamma (PPARgamma). The aim of the present study was to evaluate CDDO activity in EOC cell lines in vitro.


METHODS
The expression of PPARgamma was examined by real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) in eight EOC cell lines (2774, SKOV3, CAOV3, OVCAR3, NMP-1, HEY, 2008 and 2008.C13), and the growth inhibitory activity of CDDO was assessed using the MTT assay.


RESULTS
PPARgamma RNA was expressed in all eight cell lines examined, but the expression varied widely among cell lines. In contrast, CDDO showed a similar degree of activity in different EOC cell lines independent of cisplatin sensitivity, with 50% inhibitory concentrations ranging from 1 to 4 microM. Experiments combining CDDO with cisplatin and paclitaxel indicated weak antagonism. The growth-inhibitory activity of CDDO was unaffected by PPARgamma antagonist T007.


CONCLUSIONS
Although differences were observed in PPARgamma expression in EOC cell lines, CDDO had similar growth-inhibitory activity in all cell lines examined, indicating that the antitumor activity of CDDO in vitro is mediated by a mechanism independent of PPARgamma. The activity of CDDO in platinum-resistant cell lines is encouraging with respect to the potential clinical use of the drug.
Melichar
Bohuslav
B
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Konopleva
Marina
M
Hu
Wei
W
Melicharova
Karolina
K
Andreeff
Michael
M
Freedman
Ralph S
RS
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis*
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D009828:Oleanolic Acid