title: Antiangiogenic activity of berberine is mediated through the downregulation of hypoxia-inducible factor-1, VEGF, and proinflammatory mediators.
abstract: Berberine, a naturally occurring isoquinoline alkaloid, is present in a number of important medicinal plants. Berberine has a wide range of biochemical and pharmacological effects, including anticancer effects. In this study, we elucidated the mechanism of antiangiogenic activity of berberine using in vivo and in vitro models. In vivo antiangiogenic activity was studied using B16F-10 melanoma cells and induced capillary formation in C57BL/6 mice. Berberine, at 10 mg/kg body weight, showed significant inhibition in tumor-directed capillary formation and in various proangiogenic factors, such as vascular endothelial growth factor (VEGF), and proinflammatory mediators, such as interleukin (IL)-1β, IL-6, tumor necrosis factor alpha (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF), which are involved in tumor angiogenesis. At the same time, it could also increase antitumor factors, such as IL-2 and tissue-inhibitor metalloproteinase (TIMP) levels in the serum. Berberine could also inhibit endothelial motility, migration, tube formation, and vessel sprouting from rat aortic ring in vitro. Further, berberine inhibited various transcription factors involved in tumor development and angiogenesis, such as NF-ĸB, c-Fos, CREB, and ATF-2. mRNA expression levels of proangiogenic factors, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and hypoxia-inducible factor (HIF), were also downregulated in tumor cells after treatment with berberine. Drastically elevated expressions of HIF and VEGF mRNA by tumor cells under hypoxic conditions were also decreased after treatment with berberine. This result clearly demonstrates that the antiangiogenic activity of berberine is mainly mediated through the inhibition of various proinflammatory and pro-angiogenic factors and the major ones are HIF, VEGF, COX-2, NO, NF-ĸB, and proinflammatory cytokines.
authors.affiliation: Amala Cancer Research Center, Amala Nagar, Thrissur, India.
authors.forename: T P
authors.initials: TP
authors.lastname: Hamsa
authors.forename: Girija
authors.initials: G
authors.lastname: Kuttan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D051793:Hypoxia-Inducible Factor 1; D018836:Inflammation Mediators; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D001599:Berberine