Piperine, a dietary phytochemical, inhibits angiogenesis.
Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G(1)/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induced angiogenic activity by rat aorta explants and breast cancer cell-induced angiogenesis in chick embryos. Although piperine binds to and activates the cation channel transient receptor potential vanilloid 1 (TRPV1), its effects on endothelial cells did not involve TRPV1 since the antiproliferative effect of piperine was not affected by TRPV1-selective antagonists, nor did HUVECs express detectable TRPV1 mRNA. Importantly, piperine inhibited phosphorylation of Ser 473 and Thr 308 residues of Akt (protein kinase B), which is a key regulator of endothelial cell function and angiogenesis. Consistent with Akt inhibition as the basis of piperine's action on HUVECs, inhibition of the phosphoinositide-3 kinase/Akt signaling pathway with LY-294002 also inhibited HUVEC proliferation and collagen-induced angiogenesis. Taken together, these data support the further investigation of piperine as an angiogenesis inhibitor for use in cancer treatment.
Department of Pathology, Dalhousie University, Halifax, PO Box 15000, Nova Scotia, Canada.
Carolyn D
CD
Doucette
Ashley L
AL
Hilchie
Robert
R
Liwski
David W
DW
Hoskin
D000470:Alkaloids / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D002867:Chromones / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D016196:S Phase / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics; D013912:Threonine / Q000378:metabolism
D000470:Alkaloids; D020533:Angiogenesis Inhibitors; D052117:Benzodioxoles; D002867:Chromones; D009025:Morpholines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D013912:Threonine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; C008922:piperine