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Research Articles: Therapeutics, Targets, and Development

The synthetic oleanane triterpenoid, CDDO-methyl ester, is a potent antiangiogenic agent

¹ Multimedica IRCCS, Milan, Italy; ² University of Insubria, School of Medicine, Department of Clinical and Biological Sciences, Varese, Italy; ³ Centro Boitechnologie Avanzate, Genova, Italy; and ⁴ Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire

Requests for reprints: Michael Sporn, Dartmouth Medical School, Department of Pharmacology, 7650 Remsen, Hanover, NH 03755. Phone: 603-650-6557; Fax: 603-650-1129. E-mail: Michael.Sporn{at}Dartmouth.edu

Abstract

We show that the synthetic oleanane triterpenoid, CDDO-methyl ester (CDDO-Me; methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate) is an effective agent for suppressing angiogenesis, both in cell culture and in vivo. The potency of CDDO-Me is particularly striking when dosed in vivo to inhibit the angiogenic effects of vascular endothelial growth factor and tumor necrosis factor- in Matrigel sponge assays; activity is seen at i.p. doses of CDDO-Me as low as 0.003 mg/kg of body weight. If the Matrigel sponges are impregnated with CDDO-Me just before implantation in the mice, picomolar doses of CDDO-Me will suppress angiogenesis. CDDO-Me also inhibits growth of endothelial cells in monolayer cultures and suppresses neovascular morphogenesis in three-dimensional cultures, but significantly higher doses (50-200 nmol/L) are required. We also show antiangiogenic effects of CDDO-Me on xenografts of Kaposi's sarcoma cells in immunocompromised mice, using CD31 as a marker. Several known individual molecular targets of CDDO-Me and related triterpenoids that are relevant to all of these findings include nuclear factor-B signaling, signal transducers and activators of transcription signaling, and transforming growth factor-β signaling, as well as Keap1, the endogenous inhibitor of the transcription factor Nrf2. However, the particularly potent antiangiogenic activity seen in vivo in the present experiments suggest that CDDO-Me, as an angioprevention agent, may be interacting with an entire network of molecular and cellular targets, rather than at a single molecular locus or in a single-cell type. [Mol Cancer Ther 2007;6(12):3139–46]

Grant support: Associazione Italiana per la Ricerca sul Cancro, Ministero della Salute Progetto Integrato, MIUR PRIN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale), University of Insubria Fondi di Ateneo, U.S. NIH grant R01 CA78814, National Foundation for Cancer Research, Dartmouth Class of 1934, and Reata Pharmaceuticals.

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.

Note: N. Vannini and G. Lorusso are in the "Degenerative Disease and Immunopathology" Ph.D. program in the Faculty of Medicine, University of Insubria. The entire pharmacological development of CDDO and its derivatives, such as CDDO-Me, was generously supported by the RAID program at the National Cancer Institute.

Received 7/ 9/07; revised 9/17/07; accepted 10/23/07.

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