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The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor
The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) signaling axis has gained considerable attention as an attractive molecular target for therapeutic blockade of cancer. Inspired by the chemical structure of S (−)-oleocanthal, a natural secoiridoid from extra-virgin...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078011/ https://www.ncbi.nlm.nih.gov/pubmed/27086914 http://dx.doi.org/10.18632/oncotarget.8681 |
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author | Mohyeldin, Mohamed M. Akl, Mohamed R. Ebrahim, Hassan Y. Dragoi, Ana Maria Dykes, Samantha Cardelli, James A. El Sayed, Khalid A. |
author_facet | Mohyeldin, Mohamed M. Akl, Mohamed R. Ebrahim, Hassan Y. Dragoi, Ana Maria Dykes, Samantha Cardelli, James A. El Sayed, Khalid A. |
author_sort | Mohyeldin, Mohamed M. |
collection | PubMed |
description | The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) signaling axis has gained considerable attention as an attractive molecular target for therapeutic blockade of cancer. Inspired by the chemical structure of S (−)-oleocanthal, a natural secoiridoid from extra-virgin olive oil with documented anticancer activity against c-Met-dependent malignancies, the research presented herein reports on the discovery of the novel olive-derived homovanillyl sinapate (HVS) as a promising c-Met inhibitor. HVS was distinguished for its remarkable potency against wild-type c-Met and its oncogenic variant in cell-free assays and confirmed by in silico docking studies. Furthermore, HVS substantially impaired the c-Met-mediated growth across a broad spectrum of breast cancer cells, while similar treatment doses had no effect on the non-tumorigenic mammary epithelial cell growth. In addition, HVS caused a dose-dependent inhibition of HGF-induced, but not epidermal growth factor (EGF)-induced, cell scattering in addition to HGF-mediated migration, invasion, and 3-dimensional (3D) proliferation of tumor cell spheroids. HVS treatment effects were mediated via inhibition of ligand-mediated c-Met activation and its downstream mitogenic signaling and blocking molecular mediators involved in cellular motility across different cellular contexts. An interesting feature of HVS is its good selectivity for c-Met and Abelson murine leukemia viral oncogene homolog 1 (ABL1) when profiled against a panel of kinases. Docking studies revealed interactions likely to impart high dual affinity for both ABL1 and c-Met kinases. HVS markedly reduced tumor growth, showed excellent pharmacodynamics, and suppressed cell proliferation and microvessel density in an orthotopic model of triple negative breast cancer. Collectively, the present findings suggested that the oleocanthal-based HVS is a promising c-Met inhibitor lead entity with excellent therapeutic potential to control malignancies with aberrant c-Met activity. |
format | Online Article Text |
id | pubmed-5078011 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-50780112016-10-28 The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor Mohyeldin, Mohamed M. Akl, Mohamed R. Ebrahim, Hassan Y. Dragoi, Ana Maria Dykes, Samantha Cardelli, James A. El Sayed, Khalid A. Oncotarget Research Paper The hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) signaling axis has gained considerable attention as an attractive molecular target for therapeutic blockade of cancer. Inspired by the chemical structure of S (−)-oleocanthal, a natural secoiridoid from extra-virgin olive oil with documented anticancer activity against c-Met-dependent malignancies, the research presented herein reports on the discovery of the novel olive-derived homovanillyl sinapate (HVS) as a promising c-Met inhibitor. HVS was distinguished for its remarkable potency against wild-type c-Met and its oncogenic variant in cell-free assays and confirmed by in silico docking studies. Furthermore, HVS substantially impaired the c-Met-mediated growth across a broad spectrum of breast cancer cells, while similar treatment doses had no effect on the non-tumorigenic mammary epithelial cell growth. In addition, HVS caused a dose-dependent inhibition of HGF-induced, but not epidermal growth factor (EGF)-induced, cell scattering in addition to HGF-mediated migration, invasion, and 3-dimensional (3D) proliferation of tumor cell spheroids. HVS treatment effects were mediated via inhibition of ligand-mediated c-Met activation and its downstream mitogenic signaling and blocking molecular mediators involved in cellular motility across different cellular contexts. An interesting feature of HVS is its good selectivity for c-Met and Abelson murine leukemia viral oncogene homolog 1 (ABL1) when profiled against a panel of kinases. Docking studies revealed interactions likely to impart high dual affinity for both ABL1 and c-Met kinases. HVS markedly reduced tumor growth, showed excellent pharmacodynamics, and suppressed cell proliferation and microvessel density in an orthotopic model of triple negative breast cancer. Collectively, the present findings suggested that the oleocanthal-based HVS is a promising c-Met inhibitor lead entity with excellent therapeutic potential to control malignancies with aberrant c-Met activity. Impact Journals LLC 2016-04-11 /pmc/articles/PMC5078011/ /pubmed/27086914 http://dx.doi.org/10.18632/oncotarget.8681 Text en Copyright: © 2016 Mohyeldin et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Mohyeldin, Mohamed M. Akl, Mohamed R. Ebrahim, Hassan Y. Dragoi, Ana Maria Dykes, Samantha Cardelli, James A. El Sayed, Khalid A. The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor |
title | The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor |
title_full | The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor |
title_fullStr | The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor |
title_full_unstemmed | The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor |
title_short | The oleocanthal-based homovanillyl sinapate as a novel c-Met inhibitor |
title_sort | oleocanthal-based homovanillyl sinapate as a novel c-met inhibitor |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078011/ https://www.ncbi.nlm.nih.gov/pubmed/27086914 http://dx.doi.org/10.18632/oncotarget.8681 |
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