title: Curcumin inhibits the formation of capillary-like tubes by rat lymphatic endothelial cells.
abstract: The natural pigments curcumin and berberine have been shown to exhibit a variety of pharmacologic effects including anti-inflammatory, anti-cancer, and anti-metastatic properties. Here, we investigated the anti-lymphangiogenic effect with an in vitro tube-forming model using conditionally immortalized lymphatic endothelial TR-LE cells, a newly established cell line originating from the thoracic duct of a transgenic rat expressing the temperature-sensitive SV40 large T-antigen. Curcumin, but not berberine, exhibited a dose-dependent inhibition of the formation of capillary-like tubes by TR-LE cells without affecting cell viability and adhesion to Matrigel. To address the molecular mechanisms involved, we performed experiments with specific inhibitors against putative targets of curcumin, including IkappaB kinase (IKK), epidermal growth factor receptor (EGFR), phosphatidylinositol-3 kinase (PI3K)/Akt, and matrix metalloproteinases (MMPs). While the IKK-2 inhibitor VI and EGFR tyrosine kinase inhibitors gefitinib and PD153035 had no effect, both the PI3K inhibitor LY294002 and the MMP inhibitor GM6001 shortened the tubes by approximately 50%. Western blot analysis and gelatin zymography revealed that curcumin, but not berberine, has an inhibitory effect on the phosphorylation of Akt and enzymatic activity of MMP-2 in TR-LE cells. These results suggest that curcumin exerts its inhibitory effect on lymphangiogenesis partly through Akt and MMP-2.
authors.affiliation: Department of Anatomy, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Matsuo
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
mesh_terms: D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D002196:Capillaries; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D009362:Neoplasm Metastasis / Q000517:prevention & control; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats
chemical_list: D001599:Berberine; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D020778:Matrix Metalloproteinase 2; D003474:Curcumin