Anti-angiogenic activity of a novel class of chemopreventive compounds: oleanic acid terpenoids

Angiogenesis is the base for solid tumour growth and dissemination, and anti-angiogenic drugs have been demonstrated to be active in clinical trials. In addition, it has become increasingly clear that inflammation is a key component in tumour insurgence. Chemoprevention focuses on the primary or secondary prevention of cancer using natural or synthetic agents that usually show mild or no collateral effects. We have noted that angiogenesis, particularly 'inflammatory angiogenesis', is a common target of many chemopreventive molecules, where they most likely suppress the angiogenic switch in pre-malignant tumours, a concept we have termed 'angioprevention'. We have shown that various molecules, such as flavonoids, antioxidants and retinoids, act in the tumour microenvironment inhibiting the recruitment and/or activation of endothelial cells and phagocytes of the innate immunity. We have recently assessed the activity of novel compounds derived from the oleanolic acid triterpenoid, called CDDO-Me and CDDO-Imm. These compounds show a potent anti-angiogenic activity at low dosages. In vivo they inhibit angiogenesis in the Matrigel sponge assay and in KS-Imm (an immortalized Kaposi's sarcoma cell line) tumour growth. In vitro they are able to prevent endothelial cell tubulogenesis when cultured on Matrigel. In human umbilical vein endothelial (HUVE) cells these compounds can inhibit the activation of the extracellular signal-regulated kinase ERK1/2 pathway after stimulation with vascular endothelial growth factor (VEGF). Moreover, from immunofluorescence experiments we observed that treatment with these triterpenoids prevents nuclear factor NF-kappaB translocation into the nucleus and thereby the activation of downstream pathways. The particularly potent anti-angiogenic activity seen in vivo suggest that CDDO-Me may be interacting with an important network of molecular and cellular targets, on endothelial cells, and could be employed for 'angioprevention'. These substances are being assessed in phase I trials in humans in the United States.