Abstract B105: Inhibition of angiogenesis by oleanoleic acid-derived triterpenoids: mechanisms of action and potential prostate cancer prevention Free

B105

Angiogenesis is a limiting step for the switch from a dormant to malignant state in tumor progression. During tumor development tumor cells induce profound changes in the surrounding tissue, leading to the formation of an altered tumor microenvironment that is critical in permitting further tumor growth and tumor progression.. Angiogenesis and inflammation are common targets of many chemopreventive molecules that suppress the antiangiogenic switch in premalignant tumors.We evaluated in vitro and in vivo the antiangiogenic activity of two synthetic oleanoleic acid-derived triterpenoids under study for their chemopreventive and therapeutic potential, CDDO -Me and -Im. In vitro both compounds exhibited a strong inhibitory activity on endothelial cells isolated from umbilical veins (HUVEC). Futher, these compounds inhibited inflammatory cell chemotaxis towards specific chemokine stimului. The triterpenoids interfered with activation of the PI3K/Akt pathway following VEGF stimulation and activation of the NF-kappaB pathway subsequent to TNFalpha stimulation. Moreover CDDO-Me induces cell death in androgen-responsive and unresponsive human prostate cancer cell lines at very low concentrations, by acting agains GS3K pathway (Venè R, Larghero P, Arena G, Sporn MB, Albini A, Tosetti F. Cancer Res. 2008).In vivo CDDO-Im and especially CDDO-Me significantly inhibit neoangiogenesis in the matrigel sponge assay in C57BL mice, reducing both CD31⁺ cell number and Hb content in the sponges. We tested different schedules of treatment, by administering compounds as prevention before matrigel injection, as therapy after injection and as combination of prevention and therapy. All three protocols reduced angiogenesis when compared to controls the combinationof prevention and intervention was the most effective and at very low dosages. Since currently CDDO-Me is being assessed phase I trials in the US, the potential anti-angiogenic activity of these drugs should be taken into consideration in evaluating efficacy in these trials.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):B105.