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.
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.
Park
Byung Chul
BC
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, South Korea.
Park
Su-Young
SY
Lee
Jong-Suk
JS
Mousa
Shaker A
SA
Kim
Jong Tae
JT
Kwak
Mi-Kyoung
MK
Kang
Keon Wook
KW
Lee
Eung-Seok
ES
Choi
Han Gon
HG
Yong
Chul Soon
CS
Kim
Jung-Ae
JA
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*
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