Dysregulated activation c-Met receptor tyrosine kinase and its ligand HGF enhance cell growth, invasion, angiogenesis, metastasis, reduction of apoptosis, and change cytoskeletal functions of many tumors. Therefore, targeting c-Met activity with small molecule inhibitors of HGF/c-Met can be used for cancer treatment and prevention. The Mediterranean diet correlates with lower incidences of cardiovascular disease, age-related cognitive disease and cancer. A computer-assisted study identified (-)-oleocanthal (1), a natural secoiridoid from extra-virgin olive oil (EVOO), as a potential c-Met inhibitor hit. Oleocanthal inhibited in-vitro the phosphorylation of c-Met kinase, proliferation, migration, and invasion of te human breast and prostate cancer cell lines MCF7, MDA-MB-231 and PC-3, respectively. It also showed anti-angiogenic activity via downregulating the expression of CD31 in endothelial colony forming cells. Our long-term goal is to utilize the ability of olive oil secoiridoids like oleocantal to inhibit the activation of c-Met and use them as dietary supplements to synergize the therapeutic effects of chemotherapeutics like the dual EGFR and HER2 tyrosine kinase inhibitor (TKI) lapatinib. The present objective is to develop a new EVOO secoiridoids rich fraction (EVOOSRF) via simple extraction methodology and test the mixture and individual components'ability to inhibit the c-Met tyrosine kinase. Our central hypothesis is that dietary-based EVOOSRF and secoiridoid-related analogs can synergize the therapeutic effects of the currently used receptor TKIs when concomitantly used for c-Met dependent malignancies. The rationale for the proposed research is that gaining new knowledge concerning the mechanism and c-Met inhibitory activity of EVOO secoiridoid ingredients will facilitate the development of therapeutic approaches for remedy of c-Met-dependent malignancies. We will test our central hypothesis, and thereby accomplish the objective of this application by pursuing the following specific aims: 1: Optimization of standardized EVOO secoiridoid rich fraction. 2: Rationale design and synthesis of c-Met inhibitory tyrosol-based analogs. 3: Assessment of c-Met inhibitory, in vitro, and in vivo activities of EVOOSRF and new tyrosol analogs alone and in combination with receptor tyrosine kinase inhibitors. The expected outcomes of the work proposed in specific aims 1-3 will include the development of novel c-Met inhibitor dietary supplement (EVOOSRF) or synthetic analogs appropriate for further future preclinical and clinical studies. Anticipated new information will facilitate important therapeutic advances for alleviation and prevention of c-Met dependent malignancies.

Public Health Relevance

The Mediterranean diet correlates with lower incidences of cancer. Computer-aided study identified (-)-oleocanthal, a natural secoiridoid from extra-virgin olive oil (EVOO), as a potential c-Met inhibitor. This proposal aims at the development of EVOO secoiridoid rich fraction, individual secoiridoids and related rationally designed synthetic analog to control c-Met dependent malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15CA167475-01A1
Application #
8434417
Study Section
Special Emphasis Panel (ZRG1-OTC-X (90))
Program Officer
Ross, Sharon A
Project Start
2013-02-01
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2016-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$420,540
Indirect Cost
$120,540
Name
University of Louisiana at Monroe
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
782279541
City
Monroe
State
LA
Country
United States
Zip Code
71209
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Ebrahim, Hassan Y; Elsayed, Heba E; Mohyeldin, Mohamed M et al. (2016) Norstictic Acid Inhibits Breast Cancer Cell Proliferation, Migration, Invasion, and In Vivo Invasive Growth Through Targeting C-Met. Phytother Res 30:557-66
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Mohyeldin, Mohamed M; Akl, Mohamed R; Siddique, Abu Bakar et al. (2016) The marine-derived pachycladin diterpenoids as novel inhibitors of wild-type and mutant EGFR. Biochem Pharmacol :
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Mohyeldin, Mohamed M; Akl, Mohamed R; Ebrahim, Hassan Y et al. (2016) The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor. Oncotarget 7:32247-73
Mady, Mohamed S; Mohyeldin, Mohamed M; Ebrahim, Hassan Y et al. (2016) The indole alkaloid meleagrin, from the olive tree endophytic fungus Penicillium chrysogenum, as a novel lead for the control of c-Met-dependent breast cancer proliferation, migration and invasion. Bioorg Med Chem 24:113-22
Akl, Mohamed R; Ayoub, Nehad M; Ebrahim, Hassan Y et al. (2015) Araguspongine C induces autophagic death in breast cancer cells through suppression of c-Met and HER2 receptor tyrosine kinase signaling. Mar Drugs 13:288-311
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