(−)-Oleocanthal as a Dual c-MET-COX2 Inhibitor for the Control of Lung Cancer

Abstract

Lung cancer (LC) represents the topmost mortality-causing cancer in the U.S. LC patients have overall poor survival rate with limited available treatment options. Dysregulation of the mesenchymal epithelial transition factor (c-MET) and cyclooxygenase 2 (COX2) initiates aggressive LC profile in a subset of patients. The Mediterranean extra-virgin olive oil (EVOO)-rich diet already documented to reduce multiple malignancies incidence. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid exclusively occurring in EVOO and showed documented anti-breast and other cancer activities via targeting c-MET. This study shows the novel ability of OC to suppress LC progression and metastasis through dual targeting of c-MET and COX-2. Western blot analysis and COX enzymatic assay showed significant reduction in the total and activated c-MET levels and inhibition of COX1/2 activity in the lung adenocarcinoma cells A549 and NCI-H322M, in vitro. In addition, OC treatment caused a dose-dependent inhibition of the HGF-induced LC cells migration. Daily oral treatment with 10 mg/kg OC for 8 weeks significantly suppressed the LC A549-Luc progression and prevented metastasis to brain and other organs in a nude mouse tail vein injection model. Further, microarray data of OC-treated lung tumors showed a distinct gene signature that confirmed the dual targeting of c-MET and COX2. Thus, the EVOO-based OC is an effective lead with translational potential for use as a prospective nutraceutical to control LC progression and metastasis.

A New Definition of the Term “High-Phenolic Olive Oil” Based on Large Scale Statistical Data of Greek Olive Oils Analyzed by qNMR

“…Oleocanthal is a phenolic compound with anticancer [ 7 , 8 ] and anti-inflammatory activity similar to ibuprofen [ 9 ] able to inhibit the progress of Alzheimer’s disease [ 10 , 11 ] as well as oleuropein aglycon [ 12 ]. Oleacein presents anti-inflammatory [ 13 ] antiatherosclerotic [ 14 ] antioxidant [ 15 ] and neuroprotective activity [ 16 ].…”

Potential Uses of Olive Oil Secoiridoids for the Prevention and Treatment of Cancer: A Narrative Review of Preclinical Studies

“…Of particular note are the studies conducted in combination with other chemotherapeutic drugs (i.e., OC plus lapatinib; OC plus Tamoxifen; Oleuropein plus cisplatin or trastuzumab; Tyr plus paclitaxel) that highlighted that the addition of secoiridoids resulted in synergistic effects in reducing tumor cell proliferation [ 66 , 67 , 100 , 120 , 130 ]. Furthermore, secoiridoids have not been found to be cytotoxic for healthy cells [ 58 , 81 , 106 ].…”

“…OC, as a c-Met inhibitor, has been combined with lapatinib (LP), a dual epidermal growth factor receptor (EGFR)/HER2 inhibitor approved by the US Food and Drug Administration (FDA). Treatments with OC/LP resulted in synergistic anti-proliferative effects in HER2-positive BT-474 and SK-BR-3 breast cancer cell lines [ 67 ]. In particular, in BT-474 cells, the effect was cytostatic, as demonstrated by an increase of cells in the G1 phase in cell cycle analysis, and in SK-BR-3 cells the effect was cytotoxic, with apoptosis induction.…”

“…After treatment with OC plus LP, a greater tumor growth inhibition was observed, compared to controls, vehicle and single drugs. Furthermore, data showed the inhibition of multiple downstream survival and mitogenic signaling pathways in HER2-positive cells, including the PI3K, MAPK, and STAT pathways [ 67 ]. The same nude mouse xenograft model generated by orthotopic inoculation with BT-474 cells has been used by Siddique et al to investigate the effect of OC in breast cancer recurrence.…”

“…c-Met and COX-2 are the targets of OC involved in the suppression of lung cancer progression and metastasis, as tested in vitro and in vivo using A549 cells in a nude mouse tail vein injection model [ 71 ].…”