Cancer esearch cer Therapy : Preclinical bition of Hypoxia Inducible Factor-1 α by ydroxyphenylethanol , a Product from Olive Oil , Blocks rosomal Prostaglandin-E Synthase-1 / Vascular Endothelial R wth Factor Expression and Reduces Tumor Angiogenesis

wnloaded pose: 2-(3,4-dihydroxyphenil)-ethanol (DPE), a polyphenol present in olive oil, has been found to ate the growth of colon cancer cells, an effect presumably related to its anti-inflammatory activity. erimental Design: To further explore the effects of DPE on angiogenesis and tumor growth we igated the in vivo efficacy of DPE in a HT-29 xenograft model and in vitro activities in colon cancer xposed to interleukin-1β (IL-1β) and prostaglandin E-2 (PGE-2). ults: DPE (10 mg/kg/day for 14 days) inhibited tumor growth, reducing vessel lumina and blood ion to tumor, and diminished expression of hypoxia inducible factor-1α (HIF-1α), vascular helial growth factor (VEGF), and microsomal prostaglandin-E synthase-1 (mPGEs-1). In vitro, DPE μmol/L) neither affected cell proliferation nor induced apoptosis in HT-29 and WiDr cells. DPE ted the IL-1β–mediated increase of mPGEs-1 expression and PGE-2 generation, as it did the silencing -1α. Moreover, DPE blocked mPGEs-1–dependent expression of VEGF and inhibited endothelial ting induced by tumor cells in a coculture system. PGE-2 triggers a feed-forward loop involving α, which impinges on mPGEs-1 and VEGF expression, events prevented by DPE via extracellular –related kinase 1/2. The reduction of PGE-2 and VEGF levels, caused by DPE, was invariably associated marked decrease in HIF-1α expression and activity, independent of proteasome activity, indicating e DPE effects on tumor growth and angiogenesis are dependent on the inhibition of HIF-1α translation. clusions: We show that the in vivo DPE antitumor effect is associated with anti-inflammatory and Con antiangiogenic activities resulting from the downregulation of the HIF-1α/mPGEs-1/VEGF axis. Clin Cancer