title: (-)-Oleocanthal as a c-Met inhibitor for the control of metastatic breast and prostate cancers.
abstract: The proto-oncogene receptor tyrosine kinase c-Met encodes the high-affinity receptor for hepatocyte growth factor (HGF). Dysregulation of the HGF-c-Met pathway plays a significant oncogenic role in many tumors. Overexpression of c-Met is a prognostic indicator for some transitional cell carcinomas. Extra-virgin olive oil (EVOO) provides a variety of minor phenolic compounds with beneficial properties. (-)-Oleocanthal (1) is a naturally occurring minor secoiridoid isolated from EVOO, which showed potent anti-inflammatory activity via its ability to inhibit COX-1 and COX-2. It altered the structure of neurotoxic proteins believed to contribute to the debilitating effects of Alzheimer's disease. Computer-Assisted Molecular Design (CAMD) identified 1 as a potential virtual c-Met inhibitor hit. Oleocanthal inhibited the proliferation, migration, and invasion of the epithelial human breast and prostate cancer cell lines MCF7, MDA-MB-231, and PC-3, respectively, with an IC (50) range of 10-20 µM, and demonstrated anti-angiogenic activity via downregulating the expression of the microvessel density marker CD31 in endothelial colony forming cells with an IC (50) of 4.4 µM. It inhibited the phosphorylation of c-Met kinase IN VITRO in the Z'-LYTE™ assay, with an IC (50) value of 4.8 µM. (-)-Oleocanthal and EVOO can have potential therapeutic use for the control of c-Met-dependent malignancies.
authors.affiliation: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, Louisiana 71201, USA.
authors.forename: Ahmed Y
authors.initials: AY
authors.lastname: Elnagar
authors.forename: Paul W
authors.initials: PW
authors.lastname: Sylvester
authors.forename: Khalid A
authors.initials: KA
authors.lastname: El Sayed
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000081004:Cyclopentane Monoterpenes; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008958:Models, Molecular; D009361:Neoplasm Invasiveness / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000069463:Olive Oil; D010636:Phenols / Q000378:metabolism / Q000494:pharmacology*; D010938:Plant Oils / Q000737:chemistry; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000447:Aldehydes; D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D000081004:Cyclopentane Monoterpenes; C000715470:MAS1 protein, human; D000069463:Olive Oil; D010636:Phenols; D010938:Plant Oils; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D000090063:Proto-Oncogene Mas; D000255:Adenosine Triphosphate; C503534:oleocanthal; D011494:Protein Kinases; D019859:Proto-Oncogene Proteins c-met