title: Antitumour activity on extrinsic apoptotic targets of the triterpenoid maslinic acid in p53-deficient Caco-2 adenocarcinoma cells.
abstract: We report that a novel triterpenoid, (2a,3b)-2,3-dihydroxyolean-12-en-28-oic acid (maslinic acid), isolated from olive pomace from Olea europaea, triggers primarily the extrinsic and later the intrinsic apoptotic pathways in Caco-2 human colon-cancer cells. Apoptosis induced by maslinic acid was confirmed by FACS analysis using annexine-V FICT staining. This induction of apoptosis was correlated with the early activation of caspase-8 and caspase-3, the activation of caspase-8 was also correlated with higher levels of Bid cleavage and decreased Bcl-2, but with no change in Bax expression. Maslinic acid also induced a sustained activation of c-Jun N-terminal kinase (JNK). Incubation with maslinic acid also resulted in the later activation of caspase-9, which, together with the lack of any Bax activation, suggests that the mitochondrial pathway is not required for apoptosis induced by maslinic acid in this cell line. In this study we found that the mechanism of apoptotic activation in p53-deficient Caco-2 cells differs significantly from that found in HT-29 cells. Natural agents able to activate both the extrinsic and intrinsic apoptotic pathways by avoiding the mitochondrial resistance mechanisms may be useful for treatment against colon cancer regardless of its aetiology.
authors: Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain. Electronic address: ferjes@ugr.es.
authors: Fernando J
authors: FJ
authors: Reyes-Zurita
authors: Eva E
authors: EE
authors: Rufino-Palomares
authors: Pedro P
authors: PP
authors: Medina
authors: E
authors: E
authors: Leticia García-Salguero
authors: Juan
authors: J
authors: Peragón
authors: Marta
authors: M
authors: Cascante
authors: José A
authors: JA
authors: Lupiáñez
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D018938:Caco-2 Cells; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019073:HT29 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D008928:Mitochondria / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014315:Triterpenes / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis; D009828:Oleanolic Acid / Q000031:analogs & derivatives
chemical_list: D053148:Caspase 3; D053181:Caspase 8; D048031:JNK Mitogen-Activated Protein Kinases; D014315:Triterpenes; D051028:bcl-2-Associated X Protein; C412811:maslinic acid; D009828:Oleanolic Acid
keywords: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; 4′,6-diamidino-2-phenylindole; CDDO; Colon cancer cells; DAPI; DMEM; DMSO; Dulbecco's modified Eagle's medium; Extrinsic apoptotic pathway; FACS; FCS; MA; MMP; Maslinic acid; PI; Rh123; Triterpenes; dimethyl sulfoxide; fluorescence-activated cell sorter; foetal calf serum; maslinic acid; mitochondrial membrane potential; propidium iodide; rhodamine