Antitumour activity on extrinsic apoptotic targets of the triterpenoid maslinic acid in p53-deficient Caco-2 adenocarcinoma cells

• Published in: Biochimie Vol. 95; no. 11; pp. 2157 - 2167
• Main Authors: Reyes-Zurita, Fernando J., Rufino-Palomares, Eva E., Medina, Pedro P., Leticia García-Salguero, E., Peragón, Juan, Cascante, Marta, Lupiáñez, José A.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.11.2013
• Subjects: adenocarcinoma; anticarcinogenic activity; apoptosis; Apoptosis - drug effects; bcl-2-Associated X Protein - biosynthesis; Caco-2 Cells; Caspase 3 - biosynthesis; Caspase 8 - biosynthesis; caspase-3; caspase-8; caspase-9; Colon cancer cells; colorectal neoplasms; etiology; Extrinsic apoptotic pathway; Gene Expression Regulation, Neoplastic - drug effects; HT29 Cells; human cell lines; Humans; JNK Mitogen-Activated Protein Kinases - biosynthesis; Maslinic acid; Mitochondria - metabolism; mitogen-activated protein kinase; Olea; Olea europaea; olive pomace; resistance mechanisms; Signal Transduction - drug effects; Triterpenes; Triterpenes - pharmacology; Triterpenes; Maslinic acid; DMSO; Extrinsic apoptotic pathway; DAPI; FACS; Rh123; DMEM; MMP; CDDO; MA; FCS; Colon cancer cells; PI; mitochondrial membrane potential; 4′,6-diamidino-2-phenylindole; fluorescence-activated cell sorter; Dulbecco's modified Eagle's medium; dimethyl sulfoxide; 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; propidium iodide; foetal calf serum; rhodamine
• ISSN: 0300-9084; 1638-6183; 1638-6183
• DOI: 10.1016/j.biochi.2013.08.017

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. •First description of the extrinsic apoptotic pathway activation by maslinic acid.•Implication of the t-Bid generation in the molecular mechanism found.•In response to that occurs a secondary activation of intrinsic apoptotic pathway.•Not changes in the expression of Bax levels were found.•Agents that activate both pathways may be very important against colon cancer.