title: Grape seed extract triggers apoptosis in Caco-2 human colon cancer cells through reactive oxygen species and calcium increase: extracellular signal-regulated kinase involvement.
abstract: Grape seed extract (GSE) from Italia, Palieri and Red Globe cultivars inhibits cell growth and induces apoptosis in Caco-2 human colon cancer cells in a dose-dependent manner. In order to investigate the mechanism(s) supporting the apoptotic process, we analysed reactive oxygen species (ROS) production, intracellular Ca2+ handling and extracellular signal-regulated kinase (ERK) activation. Upon exposure to GSE, ROS and intracellular Ca2+ levels increased in Caco-2 cells, concomitantly with ERK inactivation. As ERK activity is thought to be essential for promoting survival pathways, inhibition of this kinase is likely to play a relevant role in GSE-mediated anticancer effects. Indeed, pretreatment with N-acetyl cysteine, a ROS scavenger, reversed GSE-induced apoptosis, and promoted ERK phosphorylation. This effect was strengthened by ethylene glycol tetraacetic acid-mediated inhibition of extracellular Ca2+ influx. ROS and Ca2+ influx inhibition, in turn, increased ERK phosphorylation, and hence almost entirely suppressed GSE-mediated apoptosis. These data suggested that GSE triggers a previously unrecognised ERK-based mechanism, involving both ROS production and intracellular Ca2+ increase, eventually leading to apoptosis in cancer cells.
authors: Department of Clinical and Molecular Medicine, Piazza Sassari 3, La Sapienza University, 00161 Rome, Italy.
authors: Simona
authors: S
authors: Dinicola
authors: Maria Addolorata
authors: MA
authors: Mariggiò
authors: Caterina
authors: C
authors: Morabito
authors: Simone
authors: S
authors: Guarnieri
authors: Alessandra
authors: A
authors: Cucina
authors: Alessia
authors: A
authors: Pasqualato
authors: Fabrizio
authors: F
authors: D'Anselmi
authors: Sara
authors: S
authors: Proietti
authors: Pierpaolo
authors: P
authors: Coluccia
authors: Mariano
authors: M
authors: Bizzarri
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D056604:Grape Seed Extract / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D056604:Grape Seed Extract; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium