title: Deoxycholic and chenodeoxycholic bile acids induce apoptosis via oxidative stress in human colon adenocarcinoma cells.
abstract: The continuous exposure of the colonic epithelium to high concentrations of bile acids may exert cytotoxic effects and has been related to pathogenesis of colon cancer. A better knowledge of the mechanisms by which bile acids induce toxicity is still required and may be useful for the development of new therapeutic strategies. We have studied the effect of deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) treatments in BCS-TC2 human colon adenocarcinoma cells. Both bile acids promote cell death, being this effect higher for CDCA. Apoptosis is detected after 30 min-2 h of treatment, as observed by cell detachment, loss of membrane asymmetry, internucleosomal DNA degradation, appearance of mitochondrial transition permeability (MPT), and caspase and Bax activation. At longer treatment times, apoptosis is followed in vitro by secondary necrosis due to impaired mitochondrial activity and ATP depletion. Bile acid-induced apoptosis is a result of oxidative stress with increased ROS generation mainly by activation of plasma membrane enzymes, such as NAD(P)H oxidases and, to a lower extent, PLA2. These effects lead to a loss of mitochondrial potential and release of pro-apoptotic factors to the cytosol, which is confirmed by activation of caspase-9 and -3, but not caspase-8. This initial apoptotic steps promote cleavage of Bcl-2, allowing Bax activation and formation of additional pores in the mitochondrial membrane that amplify the apoptotic signal.
authors.affiliation: Departamento de Bioquímica y Biología Molecular I, Facultad de Ciencias Químicas, Universidad Complutense, 28040, Madrid, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Ignacio Barrasa
authors.forename: Nieves
authors.initials: N
authors.lastname: Olmo
authors.forename: Pablo
authors.initials: P
authors.lastname: Pérez-Ramos
authors.forename: Angélica
authors.initials: A
authors.lastname: Santiago-Gómez
authors.forename: Emilio
authors.initials: E
authors.lastname: Lecona
authors.forename: Javier
authors.initials: J
authors.lastname: Turnay
authors.forename: M
authors.initials: M
authors.lastname: Antonia Lizarbe
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D002635:Chenodeoxycholic Acid / Q000494:pharmacology / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000473:pathology*; D003840:Deoxycholic Acid / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009336:Necrosis / Q000139:chemically induced; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D053148:Caspase 3; D053453:Caspase 9