Oleuropein inhibits key pathways involved in colon cancer and supresses associated colitis colorectal cancer in C57BL/6 mice

The beneficial effects of the secoiridoid oleuropein, mainly found in leaves of olive tree (Olea europaea), are known for a long time. Our studies are focussed on the ability of this polyphenol to protect from inflammation, especially in large intestine. We tested its effect successfully in two intestinal acute and chronic inflammatory models, using dextran sulphate sodium (DSS) [1, 2]. A chronic intestinal inflammation, together with other factors, can trigger a cancerous process, so considering our positive results and its antitumoral properties, could oleuropein prevent the occurrence of colorectal cancer (CRC) using the azoxymethane (AOM)/DSS model in C57BL/6 mice? Mice received a single i.p. injection of AOM at day 0 and three cycles of DSS starting day 7. Each cycle consisted in 7 days of DSS 1.5% followed by 14 days of drinking water. Mice were randomized in 8 treatment groups: Control (drinking water), DSS (DSS cycles), AOM (AOM injection), AOM/DSS (AOM injection and DSS cycles), O50 (50 mg/kg oleuropein in water), O100 (100 mg/kg oleuropein in water), and ASA (75 mg/kg 5-aminosalycilic acid in water). At day 63 mice were sacrificed, colons removed and submitted to macroscopical examinations. Different pathways involved in tumor development were determined by western blot. Statistical significance was determined by analysis of variance (ANOVA) and Dunnet't test. Oleuropein suppressed the growth and multiplicity of colonic tumors (84%, p < 0.01), decreased COX-2 (70%, p < 0.01) expression and reduced nuclear p65 NF-κB subunit (49%, p < 0.01). Moreover, oleuropein regulated apoptotic proteins such as Bax (30%, p < 0.05), reduced the translocation of β-catenin (49%, p < 0.01) to the nucleus and the activation of pathways implicated on growth tumor: AKT/PI3K (40%, p < 0.05) and STAT-3 phosphorylation (35%, p < 0.05). The reference drug 5-ASA was effective in preventing CRC. In conclusion, oleuropein is a promising protective agent against CRC.

Keywords: Oleuropein, phenolic, colorectal cancer, dextran sulphate sodium, azoxymethane

References:

[1] Giner et al., J Agric Food Chem 2011, 59:12882 – 12892

[2] Giner et al., J Nat Prod, 2013, 76:1113 – 1120