title: The anti-angiogenic effects of 1-furan-2-yl-3-pyridin-2-yl-propenone are mediated through the suppression of both VEGF production and VEGF-induced signaling.
abstract: Angiogenesis plays a critical role in the pathogenesis of malignant tumor growth and metastases. Since cyclooxygenase (COX)-2 expression is positively correlated with vascular endothelial growth factor (VEGF) expression and enhanced angiogenesis, COX-2 inhibitors have been focused on as angiogenesis-inhibiting drugs that may offer a complementary modality to classical strategies for cancer therapy. In this study, we evaluated the potential antiangiogenic effects of 1-furan-2-yl-3-pyridin-2-yl-propenone (FPP-3), a dual COX/5-LOX inhibitor. In HT1080 cancer cells, FPP-3 significantly suppressed release of VEGF as well as activation of NF-kappaB, a transcriptional factor required for VEGF expression. In a chick chorioallantoic membrane (CAM) assay, FPP-3 dose-dependently suppressed VEGF- and MCF-7 human breast cancer cell-induced angiogenesis. In experiments with human umbilical vein endothelial cells (HUVECs), FPP-3 dose-dependently decreased not only the cell survival and proliferation but also the tube formation and invasion using Matrigel-coated plates. Such antiangiogenic activity correlated with suppression of VEGF-induced matrix metalloproteinase (MMP)-2 expression, reactive oxygen species (ROS) production, and extracellularly regulated kinase (ERK) phosphorylation. Furthermore, in contrast to the case of NS398, a selective COX-2 inhibitor, FPP-3 did not alter the ratio of tissue factor (TF)/tissue factor pathway inhibitor (TFPI) expression, a coagulation index. These results indicate that FPP-3 could be used as an effective antiangiogenic agent without the risk of developing thrombotic complications.
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Park
authors.forename: Su-Young
authors.initials: SY
authors.lastname: Park
authors.forename: Jong-Suk
authors.initials: JS
authors.lastname: Lee
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
authors.forename: Jong Tae
authors.initials: JT
authors.lastname: Kim
authors.forename: Mi-Kyoung
authors.initials: MK
authors.lastname: Kwak
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.forename: Han Gon
authors.initials: HG
authors.lastname: Choi
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005663:Furans / Q000494:pharmacology*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D011247:Pregnancy; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013925:Thromboplastin / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C508534:1-furan-2-yl-3-pyridin-2-yl-propenone; D020533:Angiogenesis Inhibitors; D005663:Furans; D008074:Lipoproteins; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D011407:Propane