Novel angio-preventive molecules and mechanisms: A focus on synthetic triterpenoids CDDO

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Angiogenesis is necessary for solid tumor growth and dissemination and it is increasingly clear that inflammation is a key component in tumor insurgence, also involved in promoting tumor angiogenesis. We found that angiogenesis is a common and key target of many chemopreventive molecules, where they most likely suppress the angiogenic switch in pre-malignant tumors, a concept we termed "Angioprevention". We have shown that various molecules, such as flavonoids, antioxidants and retinoids, act in the tumor micro-environment inhibiting the recruitment and/or activation of endothelial cells and phagocytes of the innate immunity. N-acetyl-cysteine, the green tea flavonoid epigallocatechin-3-gallate (EGCG), xanthoumol, all prevent angiogenesis in the Matrigel sponge angiogenic assay in vivo and inhibit the growth of the highly angiogenic Kaposi's sarcoma tumor cells (KS-Imm) in nude mice. The synthetic retinoid 4-hydroxyfenretinide (4HPR) also showed anti-angiogenic effects. We have now found that Alpha lipoic acid, deguelin and hyperforin are also active. Functional genomics analyses of gene expression regulation by these compounds in primary human umbilical endothelial cells (HUVEC) in culture identified overlapping sets of genes regulated by the anti-oxidants through Affymetrix GeneChip arrays. In contrast, the ROS-producing 4HPR induced members of the TGFbeta-ligand superfamily, which, at least in part, explains its anti-angiogenic activity. The flavonoids all suppressed the IkB/NF-kB signalling pathway. The repression of the NF-kB pathway suggests anti-inflammatory effects for the anti-oxidant compounds that may also represent an indirect role in angiogenesis inhibition. Most recently we investigated the new synthetic triterpenoid CDDO-Imidazolide and Methyl Esther (CDDO-Im and CDDO Me), triterpenoids previously shown to be active agents for the control of inflammation, cell proliferation, and apoptosis. CDDOs are potent inhbitors of angiogenesis and endothelial cell function, such as growth and in vitro morphogenesis, and modulate phosphorylation of AKT. Furthermore, CDDOs reduce the growth of angiogenic tumor KS.