Olive Phenolics as c-Met Inhibitors: (-)-Oleocanthal Attenuates Cell Proliferation, Invasiveness, and Tumor Growth in Breast Cancer Models

Abstract

Dysregulation of the Hepatocyte growth factor (HGF)/c-Met signaling axis upregulates diverse tumor cell functions, including cell proliferation, survival, scattering and motility, epithelial-to-mesenchymal transition (EMT), angiogenesis, invasion, and metastasis. (-)-Oleocanthal is a naturally occurring secoiridoid from extra-virgin olive oil, which showed antiproliferative and antimigratory activity against different cancer cell lines. The aim of this study was to characterize the intracellular mechanisms involved in mediating the anticancer effects of (-)-oleocanthal treatment and the potential involvement of c-Met receptor signaling components in breast cancer. Results showed that (-)-oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7 and BT-474 while similar treatment doses were found to have no effect on normal human MCF10A cell growth. In addition, (-)-oleocanthal treatment caused a dose-dependent inhibition of HGF-induced cell migration, invasion and G1/S cell cycle progression in breast cancer cell lines. Moreover, (-)-oleocanthal treatment effects were found to be mediated via inhibition of HGF-induced c-Met activation and its downstream mitogenic signaling pathways. This growth inhibitory effect is associated with blockade of EMT and reduction in cellular motility. Further results from in vivo studies showed that (-)-oleocanthal treatment suppressed tumor cell growth in an orthotopic model of breast cancer in athymic nude mice. Collectively, the findings of this study suggest that (-)-oleocanthal is a promising dietary supplement lead with potential for therapeutic use to control malignancies with aberrant c-Met activity.

Cytotoxic Activity of Oleocanthal Isolated from Virgin Olive Oil on Human Melanoma Cells

“…Interestingly, mutated BRAF is associated with an aggressive disease phenotype (8) and our findings demonstrated that oleocanthal was able to induce cytotoxicity in both cell lines with similar IC 50 values. Our results are in line with those showing that oleocanthal inhibits the growth of human breast cancer cell lines MDA-MB-231, MCF-7, and BT-474, without affecting normal human MCF10A cell growth (9). Noteworthily, selective antitumor effect by oleocanthal has been reported to be associated, at least partially, to its ability to induce lysosomal membrane permeabilization leading to apoptosis and/or necrosis.…”

(-)-Oleocanthal rapidly and selectively induces cancer cell death via lysosomal membrane permeabilization

“…38 This study presented data implicating suppression of c-Met as a critical consequence of OC treatment although it was not clear whether LMP was involved in cell death or PARP cleavage was observed. Nonetheless, the study demonstrated that OC has similar effects in an animal model to those described in the current study with minimal effects on normal cells, thus reinforcing the potential of OC as a therapeutic agent in breast and other cancers.…”

New drugs from ancient natural foods. Oleocanthal, the natural occurring spicy compound of olive oil: a brief history

“…More recent studies, for instance those by Akl and colleagues, confirmed the anticancer effects of OC treatment in breast cancer. These authors observed that OC was able to reduce c-Met kinase activity, cell growth, migration, and invasion of breast cancer cells and tumorigenicity in a mouse model [27] (Fig. 3).…”