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The Novel Synthetic Triterpenoid, CDDO-Imidazolide, Inhibits Inflammatory Response and Tumor Growth in Vivo¹

Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755 [A. E. P., N. S., C. R. W., R. R., M. B. S.]; Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755 [T. H., Y. H., G. W. G.]; Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709 [L. M. L., J. B. S., T. M. W.]; and Department of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215 [E. R.]

	ABSTRACT

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1[2-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) is a novel synthetic triterpenoid more potent than its parent compound, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), both in vitro and in vivo. CDDO-Im is highly active in suppressing cellular proliferation of human leukemia and breast cancer cell lines (IC₅₀, 10–30 nM). In U937 leukemia cells, CDDO-Im also induces monocytic differentiation as measured by increased cell surface expression of CD11b and CD36. In each of these assays, CDDO-Im is several-fold more active than CDDO. Although CDDO and CDDO-Im both bind and transactivate peroxisome proliferator-activated receptor (PPAR) , the irreversible PPAR antagonist GW9662 does not block the ability of either CDDO or CDDO-Im to induce differentiation; moreover, PPAR-null fibroblasts are still sensitive to the growth-suppressive effects of CDDO. Thus, CDDO-Im has significant actions independent of PPAR transactivation. In addition, the rexinoid LG100268 and the deltanoid ILX23-7553 (ILX7553) synergize with CDDO and CDDO-Im to induce differentiation. In vivo, CDDO-Im is a potent inhibitor of de novo inducible nitric oxide synthase expression in primary mouse macrophages. Moreover, CDDO-Im inhibits growth of B16 murine melanoma and L1210 murine leukemia cells in vivo. The potent effects of CDDO-Im, both in vitro and in vivo, suggest it should be considered for clinical use.

	INTRODUCTION

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Derivatives of naturally occurring substances are important therapeutic agents for many types of cancer, and natural products continue to be important starting materials for drug development. Naturally occurring triterpenoids, such as oleanolic acid and ursolic acid, have weak anti-inflammatory, anticarcinogenic, and antiproliferative activities (1, 2, 3, 4) . In an effort to increase the potency of oleanolic acid and ursolic acid for their use as chemopreventive and chemotherapeutic agents, we have synthesized and tested over 220 of their derivatives, including CDDO⁴ (Fig. 1A ; Refs. 5, 6, 7 ).

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. CDDO and CDDO-Im suppress proliferation of human cancer cells. A, structures of CDDO and CDDO-Im; details of the synthesis of the triterpenoids have been described previously (5 , 15) . B, growth suppression of U937 cells. U937 cells were plated at 1 x 104 cells/ml and treated with the indicated agents for 5 days. Cells were then counted and compared with cells treated with DMSO (vehicle). C, growth suppression of MCF-7 cells. Cells were treated with the indicated agents for 3 days, and cellular proliferation was measured by incorporation of radioactive thymidine. The results are displayed as a percentage compared with cells treated with DMSO. The results shown are representative of more than three independent experiments.

Here we show that CDDO-Im is more potent than CDDO both in vitro and in vivo. CDDO-Im inhibits proliferation of human cancer cell lines in culture and induces monocytic differentiation in human leukemia cells more potently than CDDO. Furthermore, in preliminary animal studies using the L1210 leukemia and B16 melanoma models of murine cancer, CDDO-Im is significantly more active than CDDO in reducing tumor burden in vivo.

Because significant evidence indicates that the processes of inflammation and carcinogenesis share common mechanisms (16, 17, 18, 19, 20, 21) , we have also evaluated the ability of triterpenoids to block de novo synthesis of iNOS and cyclooxygenase-2 (8 , 15) . Here we show that in vivo, CDDO-Im is more potent than CDDO at inhibiting iNOS expression in primary mouse macrophages. Taken together, these results indicate that CDDO-Im is a novel synthetic triterpenoid that should be considered for further clinical development as a chemopreventive or chemotherapeutic agent.

	MATERIALS AND METHODS

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Reagents.
Details of the synthesis of CDDO and CDDO-Im (see Fig. 1 for structures) have been published previously (5 , 7 , 15) . Sources of reagents were as follows: recombinant mouse IFN- (lipopolysaccharide content, <10 pg/ml) and TGF-ß1, R&D Systems (Minneapolis, MN); polyclonal iNOS IgG, actin IgG, and peroxidase-conjugated secondary antibody, Santa Cruz Biotechnology (Santa Cruz, CA); LG100268, Ligand Pharmaceuticals (San Diego, CA); ILX23-7553 (ILX7553), ILEX Oncology (San Antonio, TX); and Cremophor-EL and nonspecific esterase assay kit, Sigma (St. Louis, MO). All drugs were dissolved in DMSO and kept at -80°C before addition to cell culture assays; final concentrations of DMSO were 0.1% or less. Serial dilutions of compounds were made in treatment media containing serum.

Cell Culture.
PPAR+/- and PPAR-/- fibroblasts have been described previously (22) . All other cell lines were purchased from American Type Culture Collection (Manassas, VA) and maintained in media (THP-1, U937, HL-60, and B16 were maintained in RPMI 1640; MCF-7 was maintained in DMEM/F12; L1210 was maintained in DMEM; and PPAR+/- and PPAR-/- fibroblasts were maintained in DMEM) supplemented with FBS (10% FBS, except for B16 and L1210 cells, for which 5% FBS was used) and penicillin/streptomycin (50 units/ml penicillin and 50 µg/ml streptomycin). All cells were incubated in 5% CO₂, except for B16 cells, which were incubated in 10% CO₂. Primary macrophages were harvested and cultured from female CD-1 mice (5–10 weeks old; Charles River Breeding Laboratories, Wilmington, MA) as described previously (23) . Thymidine incorporation assays in MCF-7 breast cancer cells and PPAR+/- and PPAR-/- fibroblasts were performed as described previously (8) .

Flow Cytometry.
For FACS analysis, 0.5 x 10⁶ cells were stained with CD11b-RPE (Dako, Carpinteria, CA) and CD36-FITC (Becton Dickinson, Franklin Lakes, NJ) antibodies and analyzed on a Becton Dickinson FACScan. IgG control antibodies (Dako) were used to determine background staining. Mean equivalent fluorescence was determined using Rainbow Calibration Particles (Spherotech Inc., Libertyville, IL) and reported as fold induction compared with cells treated with vehicle.

In Vivo iNOS Suppression.
Female CD-1 mice were injected i.p. with 2 ml of 4% thioglycollate broth to elicit peritoneal macrophages. Three days later, 0.5 µg of IFN- (dissolved in 0.2 ml of PBS containing 1 mg/ml BSA) was injected i.p. to activate these macrophages. Thirty min after IFN- injection, either 1 or 10 nmol of triterpenoid (0.1 ml in 10% DMSO in PBS) were injected i.p., and 10 h later, peritoneal macrophages were harvested and cultured. After 12 h in culture, cells were assayed for levels of iNOS (Western blot) and production of NO, as described previously (23) .

L1210 and B16 Animal Studies.
For all studies, male and female BDF-1 mice (20–25 g, approximately 2 months old; Charles River Laboratories) were used. For L1210 leukemia experiments, 10 million cultured cells were injected i.p. on day 0. Three days later, treatment with the indicated agents began by twice daily i.p. injection (0.1 ml). On day 8, animals were euthanized by CO₂ narcosis; the peritoneum was flushed with 10 ml of PBS, and tumor burden was measured by counting total L1210 cells in the lavage. For B16 melanoma studies, 2 or 3 million cultured cells were injected i.p. on day 0. One to 4 days later, mice were injected i.p. twice daily with triterpenoids dissolved in a solution of DMSO, Cremophor-EL, and PBS (1:1:8). On day 8 or 9, all tumors of significant size were harvested from the peritoneal cavity and weighed to determine tumor burden. Melanomas were the only black objects in the peritoneal cavity. No metastases were seen in other organs at this early time point.

	RESULTS

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CDDO-Im Inhibits Cellular Proliferation of Human Cancer Cell Lines.
U937, THP-1, and HL-60 leukemia cells were treated with either control vehicle, CDDO, or CDDO-Im at concentrations ranging from 100 pM to 1 µM, and after 5 days, proliferation was measured by cell counting. Fig. 1B shows that CDDO-Im inhibits proliferation of U937 cells more potently than CDDO (IC₅₀, 10 versus 200 nM, respectively). Similar results were also obtained using HL-60 and THP-1 cells (data not shown). In MCF-7 human breast cancer cells, CDDO and CDDO-Im were both effective inhibitors of cellular proliferation, as measured by thymidine incorporation, and CDDO-Im was again the more potent agent [IC₅₀, 30 nM (CDDO-Im) versus 100 nM (CDDO); Fig. 1C ].

CDDO-Im and CDDO Induce Monocytic Differentiation in U937 Cells.
We have shown previously (8) that CDDO can induce monocytic differentiation in the human leukemia cell line LCBD, as measured by the induction of nonspecific esterase. We have continued these studies in U937 cells, and we have used CD11b (Mac-1, CR3 complement receptor) and CD36 (TSP-R, scavenger receptor) cell surface antigens as markers of monocytic differentiation (24 , 25) . These markers are only weakly expressed on U937 cells but can be induced with various differentiating agents including 12-O-tetradecanoylphorbol-13-acetate (26) . We measured CD11b by FACS analysis on U937 cells after 5 days of treatment with CDDO (30–300 nM) and CDDO-Im (10–100 nM); the results are shown in Fig. 2A . CDDO-Im (100 nM) caused nearly a 7-fold induction of CD11b, whereas 300 nM CDDO increased expression only by 3-fold. Fig. 2B shows that CDDO-Im was also more potent than CDDO in inducing expression of CD36 because 3 days of treatment with CDDO-Im (100 nM) increased CD36 3.5-fold, whereas CDDO was ineffective, even at doses as high as 300 nM.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. CDDO-Im is a potent inducer of monocytic differentiation. U937 cells were plated at 1 x 105 cells/ml and treated with CDDO or CDDO-Im at the indicated concentrations for 5 days. CD11b (A) and CD36 (B) expression was measured by FACS analysis. Three independent experiments were performed, and the averaged results are summarized here as fold induction compared with cells treated with DMSO (vehicle).

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. CDDD-Im synergizes with ligands for RXR and VDR in inducing differentiation. U937 cells were treated with CDDO or CDDO-Im alone and in combination with LG268 (A) or ILX7553 (B) for 5 days, and CD11b expression was analyzed by FACS analysis. In A, three independent experiments were performed, and the averaged results are summarized as fold induction compared with cells treated with DMSO. For B, results are representative of at least three similar experiments.

Effects of CDDO and CDDO-Im on Leukemia Cell Growth and Differentiation Are Independent of PPAR Activity.
CDDO is known to bind (K_i = 310 nM) and activate the nuclear receptor PPAR (14) . Fig. 4A shows that CDDO-Im also binds to PPAR with similar affinity to CDDO (K_i = 344 nM). Moreover, as shown in Fig. 4B , CDDO-Im also binds the nuclear receptor PPAR (K_i = 232 nM) with higher affinity than CDDO (K_i = 1 µM). To evaluate whether PPAR mediates the differentiative effects of CDDO-Im on U937 cells, the irreversible PPAR antagonist GW9662 (31 , 32) was used to inhibit receptor activity. U937 cells were pretreated for 2 h with GW9662 (1 and 10 µM) and then treated with CDDO-Im (100 nM) for 3 days, followed by FACS analysis of CD11b and CD36. GW9662 neither blocked expression of CD11b or CD36 induced by CDDO-Im (Fig. 4C) nor reversed inhibition of cellular proliferation caused by CDDO-Im (data not shown). As a positive control, we found that GW9662 (1 µM) completely blocked transactivation of PPAR by CDDO-Im in luciferase assays conducted in CV-1 cells (data not shown).

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. CDDO and CDDO-Im inhibit cell growth and induce differentiation independent of PPAR transactivation. A and B, CDDO-Im binds PPAR and PPAR. Scintillation proximity assays were performed as described previously (14 , 53) to measure affinity of CDDO-Im for PPAR (A) and PPAR (B). C, GW9662 does not inhibit CD11b or CD36 expression induced by CDDO-Im. U937 cells were treated with the irreversible PPAR antagonist GW9662 (1 and 10 µM) for 2 h, followed by treatment with CDDO-Im for 3 days. Cells were then analyzed for CD11b and CD36 expression by FACS analysis. The results shown here are representative of three independent experiments. D, PPAR-null fibroblasts are sensitive to growth suppression by CDDO. PPAR--/+ (upper set) and PPAR-/- (lower set) fibroblasts were treated with either triterpenoids (0.001–1 µM) or rosiglitazone (0.01–10 µM) for 2 days. Cellular proliferation was then measured by incorporation of radioactive thymidine. Results are shown as a percentage compared with DMSO-treated cells and are representative of three independent experiments.

Synthetic Triterpenoids Suppress Activation of Macrophages in Vivo.
In cell culture studies we have shown previously (8 , 15) that CDDO-Im is markedly more active than CDDO for inhibition of iNOS expression in primary mouse macrophages stimulated with IFN- and/or tumor necrosis factor . We therefore wished to determine whether similar results could be obtained in vivo. To do this, we injected mice i.p. with thioglycollate, and the resulting resident peritoneal macrophages were activated 3 days later with an i.p. injection of IFN-. CDDO and CDDO-Im were injected i.p. 30 min after IFN-. Macrophages were harvested 10 h later, cultured for 12 h, and then assayed for expression of iNOS protein and production of nitric oxide (NO). As shown in Fig. 5A , injection of 10 nmol (5.4 µg) of CDDO-Im almost completely blocked the ability of IFN- to induce iNOS, and treatment with as little as 1 nmol of CDDO-Im (0.54 µg) was partially effective. In contrast, 10 nmol (4.9 µg) of CDDO only weakly reduced expression of iNOS, and 1 nmol (0.49 µg) of CDDO was ineffective. These results were confirmed by measuring NO concentrations in the culture medium of the primary macrophages; as shown in Fig. 5B , CDDO-Im was again more potent than CDDO.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Fig. 5. CDDO-Im is more potent than CDDO for in vivo inhibition of iNOS expression. Thirty min after peritoneal macrophages were activated in CD-1 mice by IFN- (0.5 µg) injection (i.p.), CDDO and CDDO-Im were injected i.p. (1 and 10 nmol), and macrophages were harvested and cultured as described previously (23) . A, CDDO and CDDO-Im decrease expression of iNOS protein. Levels of iNOS protein in primary mouse macrophages were measured by Western blot analysis. Western blot analysis of actin was used as an internal loading control. Densitometry was performed for quantification (control, 100%; 1 nmol of CDDO-Im, 49%; 10 nmol of CDDO-Im, 2%; 1 nmol of CDDO, 100%; 10 nmol of CDDO, 64%.) B, CDDO and CDDO-Im inhibit NO production in primary mouse macrophages. NO in the cell culture medium was measured by Griess reaction.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Fig. 6. CDDO-Im is more potent than CDDO for in vivo inhibition of tumor burden. A, CDDO-Im is more potent than CDDO in inhibition of L1210 leukemia tumor burden. Ten million L1210 cells were injected in BDF-1 mice. Three days later, treatments began with twice daily injections (i.p.) of 50 µg of CDDO or CDDO-Im (100 µg/day) for 5 consecutive days. L1210 cells were then harvested from the peritoneum and counted. B, CDDO-Im is more potent than CDDO in B16 melanoma tumor burden. Two million B16 melanoma cells were injected i.p. in BDF-1 mice. Three days later, injections (i.p., twice daily) of CDDO and CDDO-Im (100 and 200 µg/day) began and continued for 5 days. Tumors were then harvested from the peritoneal cavity and weighed. C, low-dose CDDO-Im is an effective inhibitor of tumor cell growth. BDF-1 mice were injected i.p. with 3 million B16 melanoma cells. One day later, injections (i.p., twice daily) of CDDO-Im (50, 100, and 200 µg/day) began and continued for 7 days. Tumors were then harvested from the peritoneal cavity and weighed. Statistical analysis was performed by t test; asterisk signifies P < 0.05. See Tables 1 2 3 for details of statistics and animal weights.

	DISCUSSION

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CDDO-Im is approximately 10-fold more potent than CDDO as an inhibitor of human cancer cell proliferation and inducer of differentiation in human leukemia cells. Interestingly, CDDO-Im was found to synergize strongly with ligands for RXR and VDR nuclear receptors in inducing monocytic differentiation in U937 cells. Nuclear receptors control cancer cell growth and differentiation (34, 35, 36) , and their pharmacological modulation has become increasingly important in the treatment and prevention of some forms of cancers such as those of the breast and prostate, as well as acute promyelocytic leukemia. The mechanism of the synergy between CDDO-Im and ligands for RXR and VDR is not currently understood; future studies should explore in vivo applications.

The potent in vitro activities of CDDO-Im suggested that we perform studies in animals to observe the in vivo activities of this agent. We demonstrate here that CDDO-Im is more potent than CDDO at decreasing tumor burden in two distinct murine cancer models. Importantly, the concentrations of CDDO-Im that showed efficacy in these experiments were relatively nontoxic. Furthermore, we show here that CDDO-Im potently inhibits the inflammatory response in vivo (Fig. 5) as measured by inhibition of de novo iNOS protein expression in mouse macrophages. Inflammation and deregulation of inflammatory signaling pathways have been identified as contributing factors in the process of carcinogenesis, whereas inhibition of inflammation has shown significant efficacy in prevention (18 , 37, 38, 39, 40) .

Our previous studies have attempted to identify the target by which triterpenoids influence growth suppression, cell differentiation, and inflammation, and these studies have shown that CDDO binds and activates the nuclear receptor PPAR (14) . Here we investigated whether the increased potency of CDDO-Im was a result of increased affinity for this receptor. Using a scintillation proximity assay, we show that CDDO-Im binds to PPAR with an affinity similar to CDDO. However, by inhibiting PPAR activity pharmacologically and using PPAR-/- fibroblasts, we have shown that the growth-suppressive and differentiative activities of CDDO-Im are independent of PPAR transactivation (Fig. 4) . Interestingly, CDDO-Im was also found to bind PPAR, and future studies will investigate whether modulation of this receptor contributes to the growth-suppressive and differentiative activities of this agent.

In an effort to understand the mechanism by which triterpenoids influence the inflammatory response, recent studies in our laboratory have identified that CDDO-Im enhances TGF-ß signaling (41) . Like CDDO and CDDO-Im, TGF-ß has been shown to suppress cellular proliferation and induce apoptosis and differentiation in numerous cell systems (42, 43, 44, 45) . These results suggest that triterpenoids may influence growth suppression and differentiation by modulating TGF-ß signaling. Furthermore, many reports have described interactions between TGF-ß signaling and nuclear hormone receptor activity (46, 47, 48, 49, 50, 51, 52) , and future studies will determine whether the synergy between CDDO-Im and ligands for RXR and VDR may be related to these interactions.

The development of synthetic triterpenoids has generated compounds with intriguing effects on biological systems closely involved in carcinogenesis and cancer therapy, namely, inflammation, proliferation, and differentiation. To date, the in vivo anti-inflammatory and antitumor activities of CDDO-Im are the most potent of any synthetic triterpenoid developed in our laboratories. The basis for the greater potency of CDDO-Im, as compared with CDDO, is not understood at present. Elucidation of the answer to this problem will depend on the identification of the true receptor, which is presently unknown, that mediates their anti-inflammatory and antiproliferative activities. As this development continues, future studies will determine both the molecular targets and pharmacokinetic profiles of these compounds. Moreover, it will be important to extend the in vivo studies on the ability of CDDO-Im to cause regression of experimental cancers to other systems that have greater relevance for treatment of human cancer. Most notably, we need to know whether CDDO-Im might have applications for treating common carcinomas, such as those of the lung, colon, breast, prostate, pancreas, and ovary. Furthermore, the potential of CDDO to act as a chemopreventive agent for carcinomas at these sites needs to be evaluated in animal models. However, despite the limitations of the data at hand, the increased potency and in vivo activities of CDDO-Im suggest that this novel synthetic triterpenoid should now be considered for clinical prevention or treatment of cancer. Additional studies on the pharmacokinetics and toxicology of CDDO-Im are now critically needed before any clinical trials can begin. Such studies are currently in progress and will be the subject of future reports.

	ACKNOWLEDGMENTS

 
We thank Ed Sausville and Ken Snader (National Cancer Institute RAID Program) for CDDO and Rich Heyman and Corey Levenson for LG268 and ILX7553, respectively. We also thank members of Dartmouth College Class of 1934 for their generous support of this project and Bruce Spiegelman for helpful discussions.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported in part by NIH Grant R01 CA78814, the National Foundation for Cancer Research, the Oliver and Jennie Donaldson Trust, and two DOD/AMRD Awards, DAMD17-98-1-8604 and 17-99-1-9168. M. B. S. is Oscar M. Cohn Professor.

² Both authors contributed equally to this work.

³ To whom requests for reprints should be addressed, at Department of Pharmacology, Dartmouth Medical School, Remsen 524, Hanover, NH 03755.

⁴ The abbreviations used are: CDDO, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid; CDDO-Im, 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole; PPAR, peroxisome proliferator-activated receptor; iNOS, inducible nitric oxide synthase; RXR, retinoid X receptor; VDR, vitamin D receptor; TGF, transforming growth factor; FACS, fluorescence-activated cell-sorting.

Received 12/10/02; revised 2/20/03; accepted 2/27/03.

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