title: Rottlerin exhibits antiangiogenic effects in vitro.
abstract: Rottlerin, a natural product purified from Mallotus philippinensis, has a number of target molecules and biological effects. We recently found that Rottlerin caused growth arrest in MCF-7 breast cancer cells and human immortalized keratinocytes, through inhibition of NFκB and downregulation of cyclin D-1. To evaluate whether this effect could be generalized to primary cells, human microvascular endothelial cells were treated with Rottlerin. In this study, we demonstrated that Rottlerin prevents basal and TNFα-stimulated NFκB nuclear migration and DNA binding also in human microvascular endothelial cell, where NFκB inhibition was accompanied by the downregulation of NFκB target gene products, such as cyclin D-1 and endothelin-1, which are essential molecules for endothelial cell proliferation and survival. Rottlerin, indeed, inhibited human microvascular endothelial cells proliferation and tube formation on Matrigel. Rottlerin also increases cytoplasmic free calcium and nitric oxide levels and downregulates endothelin converting enzyme-1 expression, thus contributing to the drop in endothelin-1 and growth arrest. These results suggest that Rottlerin may prove useful in the development of therapeutic agents against angiogenesis.
authors: Department of Biomedical Sciences, University of Siena, Italy.
authors: Giuseppe
authors: G
authors: Valacchi
authors: Alessandra
authors: A
authors: Pecorelli
authors: Claudia
authors: C
authors: Sticozzi
authors: Claudia
authors: C
authors: Torricelli
authors: Michela
authors: M
authors: Muscettola
authors: Carlo
authors: C
authors: Aldinucci
authors: Emanuela
authors: E
authors: Maioli
mesh_terms: D000098:Acetophenones / Q000494:pharmacology*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001578:Benzopyrans / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000235:genetics; D004247:DNA / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000235:genetics; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000166:cytology*; D005786:Gene Expression Regulation; D006801:Humans; D036461:Mallotus Plant / Q000737:chemistry*; D008666:Metalloendopeptidases / Q000235:genetics; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009589:Nitrogen Oxides / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000098:Acetophenones; D020533:Angiogenesis Inhibitors; D001578:Benzopyrans; D019332:Endothelin-1; D016328:NF-kappa B; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; D004247:DNA; C085746:rottlerin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes; D002118:Calcium