Role of protein kinase C-dependent signaling pathways in the antiangiogenic properties of nafoxidine.
We analyzed the effect of nafoxidine on the earlier biological processes of angiogenesis and explored the role of different signaling pathways involved in the in vitro response of endothelial cells (HUVEC). Nafoxidine significantly inhibited adhesion, spreading, migration and invasion of HUVEC at concentrations ranging from 1 to 2.5 microM. Endothelial cord formation on Matrigel was inhibited by nafoxidine and cotreatment with phorbol-12-myristate-13-acetate (PMA) clearly prevented the antiangiogenic effect of the antiestrogen. On the contrary, cotreatment with the PKC inhibitor bisindolylmaleimide potentiated inhibition of cord formation. PMA also inhibited the nafoxidine-induced secretion of metalloproteinase-2 and tissue inhibitor of metalloproteinases-1 in HUVEC monolayers. Cotreatment with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and the cAMP analog N6,2'-o-dibutyryladenosine 3',5'-cyclic monophosphate prevented the inhibition of endothelial cord formation induced by nafoxidine. Our work presents evidence about the signaling pathways involved in the antiangiogenic effect of nafoxidine, suggesting that PKC-dependent signaling pathways are essential in angiogenesis during endothelial cord formation.
De Lorenzo
Mariana S
MS
Laboratory of Molecular Oncology, Department of Science and Technology, Quilmes National University, Buenos Aires, Argentina.
Farina
Hernan G
HG
Alonso
Daniel F
DF
Gomez
Daniel E
DE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009256:Nafoxidine / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011493:Protein Kinase C / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D020533:Angiogenesis Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D009256:Nafoxidine; D011493:Protein Kinase C; D020778:Matrix Metalloproteinase 2