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Olive Oil‐derived Oleocanthal as Potent Inhibitor of Mammalian Target of Rapamycin: Biological Evaluation and Molecular Modeling Studies
Author(s) -
Khanfar Mohammad A.,
Bardaweel Sanaa K.,
Akl Mohamed R.,
El Sayed Khalid A.
Publication year - 2015
Publication title -
phytotherapy research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.019
H-Index - 129
eISSN - 1099-1573
pISSN - 0951-418X
DOI - 10.1002/ptr.5434
Subject(s) - pi3k/akt/mtor pathway , neuroprotection , pharmacology , discovery and development of mtor inhibitors , chemistry , downregulation and upregulation , biochemistry , biology , signal transduction , gene
The established anticancer and neuroprotective properties of oleocanthal combined with the reported role of mammalian target of rapamycin (mTOR) in cancer and Alzheimer's disease development encouraged us to examine the possibility that oleocanthal inhibits mTOR. To validate this hypothesis, we docked oleocanthal into the adenosine triphosphate binding pocket of a close mTOR protein homologue, namely, PI3K‐γ. Apparently, oleocanthal shared nine out of ten critical binding interactions with a potent dual PIK3‐γ/mTOR natural inhibitor. Subsequent experimental validation indicated that oleocanthal indeed inhibited the enzymatic activity of mTOR with an IC 50 value of 708 nM. Oleocanthal inhibits the growth of several breast cancer cell lines at low micromolar concentration in a dose‐dependent manner. Oleocanthal treatment caused a marked downregulation of phosphorylated mTOR in metastatic breast cancer cell line (MDA‐MB‐231). These results strongly indicate that mTOR inhibition is at least one of the factors of the reported anticancer and neuroprotective properties of oleocanthal. Copyright © 2015 John Wiley & Sons, Ltd.