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-γ expression
Introduction
Epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic cancers [1]. Surgery alone is a therapeutic option for only a few patients who present with stage 1A disease. The introduction of paclitaxel combined with platinum-based chemotherapy has led to improvements in progression-free and overall survival rates, but the tumor ultimately recurs in most patients. The incurability of EOC in most patients necessitates the search for new drugs with activity against this tumor.
2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) is a novel synthetic triterpenoid with antitumor activity against a wide range of tumor cell lines in vitro [2]. CDDO has been shown to act through several mechanisms, including inhibiting carcinogenesis and tumor growth, inhibiting inducible nitric oxide synthase, cyclooxygenase 2 [2], and matrix metalloproteinases 1 and 13 [3], and inducing cell differentiation [2] and apoptosis [4], [5]. CDDO is also a ligand (partial agonist) for the peroxisome proliferator-activated receptor-γ (PPARγ) [6]. A high level of expression of PPARγ, a ligand-activated transcription factor that belongs to the nuclear receptor superfamily, is found in many human tumors and tumor cell lines [7], [8], [9] and may represent an important target for anticancer drugs [10], [11], [12]. Antitumor activity has been described for full agonists (e.g., thiazolidinediones antidiabetic drugs, such as rosiglitazone) [7], [13], partial agonists (e.g., CDDO) [2], and full antagonists (e.g., methyl ester of CDDO) [14] of PPARγ.
To evaluate the potential efficacy of CDDO in patients with EOC, we examined the growth-inhibitory activity of the drug as well as the expression of PPARγ in a panel of eight EOC cell lines.
Section snippets
Reagents
CDDO was manufactured through the NCI Rapid Access to Intervention Development (RAID) program and provided by Dr. Edward Sausville (National Cancer Institute, Bethesda, MD). Stock solutions of 10 nM CDDO [2] were made in dimethyl sulfoxide, and aliquots were stored at −20°C. Paclitaxel and cisplatin were obtained from Bristol-Myers Squibb (Princeton, NJ). Rosiglitazone was purchased from Cayman Chemical Company (Ann Arbor, MI). T0070907 (T007), a selective PPARγ antagonist [15], was synthesized
Results
CDDO inhibited growth in all EOC cell lines examined, with the mean IC50 ranging from 1 to 4 μM (Table 1, Fig. 1). A similar activity was observed in platinum-sensitive and platinum-resistant cell lines. The mean IC50 values for the 2008 cell line and its cisplatin-resistant subline 2008.C13 and for OVCAR3 and its cisplatin-resistant subline NMP-1 were similar. The experiments combining CDDO with cisplatin and paclitaxel indicated weak antagonism. The combination indices in 2774 cells for
Discussion
CDDO in micromolar concentrations showed a similar degree of activity in different EOC cell lines independent of cisplatin sensitivity. The activity of CDDO in EOC cell lines in this study was mostly slightly lower than CDDO's activity in a panel of different tumor cell lines in an earlier study [2]. The latter-reported IC50 ranges from 3 × 108 to 1 × 106 μM. Among 19 human cell lines examined, the IC50 of one EOC cell line (SW626) was 3 × 107 μM. In contrast to differences of almost two orders
Acknowledgements
Supported in part by grants PO1 CA55164 and RO1 CA89346 from the National Institutes of Health.
References (23)
- et al.
PPAR-γ agonists: therapeutic role in diabetes, inflammation and cancer
Trends Pharmacol. Sci.
(2000) - et al.
Troglitazone and related compounds. Therapeutic potential beyond diabetes
Life Sci.
(2000) - et al.
Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia
Blood
(2002) - et al.
T0070907, a selective ligand for peroxisome proliferator-activated receptor γ, function as an antagonist of biochemical and cellular activities
J. Biol. Chem.
(2002) - et al.
Quantitative analysis of dose–effect relationships: the combined effects of multiple drugs or enzyme inhibitors
Adv. Enzyme Regul.
(1984) - et al.
Peroxisome proliferator-activated receptor γ ligands are potent inhibitors of angiogenesis in vitro and in vivo
J. Biol. Chem.
(1999) - et al.
Cancer statistics 2001
CA Cancer J. Clin.
(2001) - et al.
A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity
Cancer Res.
(1999) - et al.
A synthetic triterpenoid selectively inhibits the induction of matrix metalloproteinases 1 and 13 by inflammatory cytokines
Arthritis Rheum.
(2001) - et al.
The novel triterpenoid 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid induces apoptosis of human myeloid leukemia cells by a caspase-8-dependent mechanism
Cell Growth Differ.
(2000)