title: Piperine, an alkaloid from black pepper, inhibits growth of human colon cancer cells via G1 arrest and apoptosis triggered by endoplasmic reticulum stress.
abstract: Piperine, a piperidine alkaloid present in black pepper, inhibits the growth of cancer cells, although the mechanism of action is not well understood. In this study, we show that piperine (75-150 µM) inhibited the growth of several colon cancer cell lines but had little effect on the growth of normal fibroblasts and epithelial cells. Piperine inhibited HT-29 colon carcinoma cell proliferation by causing G1 phase cell cycle arrest that was associated with decreased expression of cyclins D1 and D3 and their activating partner cyclin-dependent kinases 4 and 6, as well as reduced phosphorylation of the retinoblastoma protein and up-regulation of p21/WAF1 and p27/KIP1 expression. In addition, piperine caused hydroxyl radical production and apoptosis that was partially dependent on the production of reactive oxygen species. Piperine-treated HT-29 cells showed loss of mitochondrial membrane integrity and cleavage of poly (ADP-ribose) polymerase-1, as well as caspase activation and reduced apoptosis in the presence of the pan-caspase inhibitor zVAD-FMK. Increased expression of the endoplasmic reticulum stress-associated proteins inositol-requiring 1α protein, C/EBP homologous protein, and binding immunoglobulin protein, and activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, as well as decreased phosphorylation of Akt and reduced survivin expression were also observed in piperine-treated HT-29 cells. Furthermore, piperine inhibited colony formation by HT-29 cells, as well as the growth of HT-29 spheroids. Cell cycle arrest and endoplasmic reticulum stress-associated apoptosis following piperine treatment of HT-29 cells provides the first evidence that piperine may be useful in the treatment of colon cancer.
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Yaffe
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Melanie R
authors.initials: MR
authors.lastname: Power Coombs
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Carolyn D
authors.initials: CD
authors.lastname: Doucette
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Walsh
authors.affiliation: Department of Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.|Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: David W
authors.initials: DW
authors.lastname: Hoskin
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D052117:Benzodioxoles / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D029222:Piper nigrum / Q000737:chemistry; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077022:Survivin; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000470:Alkaloids; C107489:BIRC5 protein, human; D052117:Benzodioxoles; D016213:Cyclins; D051034:Inhibitor of Apoptosis Proteins; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D016755:Proto-Oncogene Proteins c-jun; D017382:Reactive Oxygen Species; D000077022:Survivin; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C008922:piperine
keywords: caspase; cell cycle; cytotoxicity; phytochemical; stress-associated protein kinase