We previously showed pomegranate seed oil and fermented juice polyphenols to retard oxidation and prostaglandin synthesis, to inhibit breast cancer cell proliferation and invasion, and to promote breast cancer cell apoptosis. Here we evaluated the anti-angiogenic potential of these materials in several ways. We checked a possible effect on angiogenic regulation by measuring vascular endothelial growth factor (VEGF), interleukin-4 (IL-4) and migration inhibitory factor (MIF) in the conditioned media of estrogen sensitive (MCF-7) or estrogen resistant (MDA-MB-231) human breast cancer cells, or immortalized normal human breast epithelial cells (MCF-10A), grown in the presence or absence of pomegranate seed oil (SESCO) or fermented juice polyphenols (W). VEGF was strongly downregulated in MCF-10A and MCF-7, and MIF upregulated in MDA-MB-231, overall showing significant potential for downregulation of angiogenesis by pomegranate fractions. An anti-proliferative effect on angiogenic cells was shown in human umbilical vein endothelial cell (HUVEC) and in myometrial and amniotic fluid fibroblasts, and inhibition of HUVEC tubule formation demonstrated in an in vitro model employing glass carrier beads. Finally, we showed a significant decrease in new blood vessel formation using the chicken chorioallantoic membrane (CAM) model in vivo. 'In sum, these varied studies employing different models in different laboratories overall demonstrate for the first time an anti-angiogenic potential of pomegranate fractions, suggesting further in vivo and clinical investigations (for updates: info@rimonest.com).
The cyclooxygenase (COX) family of enzymes has been implicated in cell proliferation and angiogenesis in many tumors, including colon cancer. Indeed, cyclooxygenase-2 (COX-2) inhibitors recently have been approved for use for prophylaxis in individuals with familial adenomatous polyposis. We now report on the effects of a selective COX-2 inhibitor, celecoxib, on cell proliferation, matrix metalloproteinase (MMP) concentration, angiogenesis using an in vitro assay, and apoptosis in several human cancer cell lines. We demonstrate that celecoxib modestly reduces proliferation in some cell lines and does not affect MMP concentrations. However, celecoxib significantly decreases microtubule formation in stimulated human umbilical vein endothelial cells (HUVECs) exposed to cancer cell supernatants, an in vitro angiogenesis model, when compared to controls incubated with supernatants from untreated cells. Celecoxib does not consistently induce apoptosis in these cell lines, as determined by DNA laddering in agarose gels and by a caspase assay. Thus, it appears that COX-2 inhibitors have beneficial effects in reducing malignant cell behavior in vitro and warrant further study to elucidate their mechanisms of action and to examine their mechanisms of action in this role and their utility in vivo in a variety of animal and human tumors.
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