Endoplasmic reticulum targeting in Ewing's sarcoma by the alkylphospholipid analog edelfosine
| Autor: | Ximena Bonilla, El Habib Dakir, Faustino Mollinedo, Consuelo Gajate |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Red Temática de Investigación Cooperativa en Cáncer (España), Instituto de Salud Carlos III, Junta de Castilla y León, European Commission, Ministerio de Ciencia e Innovación (España) |
| Rok vydání: | 2015 |
| Předmět: |
Antineoplastic Agents
Bone Neoplasms ComputingMilieux_LEGALASPECTSOFCOMPUTING Apoptosis Mice SCID Sarcoma Ewing Xenograft animal model Mice chemistry.chemical_compound In vivo Animals Humans Medicine Edelfosine biology business.industry Cytochrome c Endoplasmic reticulum Phospholipid Ethers Ewing's sarcoma Perifosine Xenograft Model Antitumor Assays In vitro 3. Good health Oncology chemistry Immunology Cancer research biology.protein Unfolded protein response Ether phospholipid Ewing’s sarcoma business Research Paper |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Scopus-Elsevier Oncotarget |
| Popis: | This is an open-access article distributed under the terms of the Creative Commons Attribution License. Ewing’s sarcoma (ES) is the second most common bone cancer in children and young people. Edelfosine (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine) is the prototype of a family of synthetic antitumor compounds, collectively known as alkylphospholipid analogs (APLs). We have found that APLs ranked edelfosine>perifosine>erucylphosphocholine>miltefosine for their capacity to promote apoptosis in ES cells. Edelfosine accumulated in the endoplasmic reticulum (ER) and triggered an ER stress response that eventually led to caspase-dependent apoptosis in ES cells. This apoptotic response involved mitochondrial-mediated processes, with cytochrome c release, caspase-9 activation and generation of reactive oxygen species. Edelfosine-induced apoptosis was also dependent on sustained c-Jun NH2-terminal kinase activation. Oral administration of edelfosine showed a potent in vivo antitumor activity in an ES xenograft animal model. Histochemical staining gave evidence for ER stress response and apoptosis in the ES tumors isolated from edelfosine-treated mice. Edelfosine showed a preferential action on ES tumor cells as compared to non-transformed osteoblasts, and appeared to be well suited for combination therapy regimens. These results demonstrate in vitro and in vivo antitumor activity of edelfosine against ES cells that is mediated by caspase activation and ER stress, and provide the proof of concept for a putative edelfosine- and ER stress-mediated approach forES treatment. This work was funded by grants from Spanish Ministerio de Ciencia e Innovación (SAF2011-30518, SAF2014-59716-R), European Community’s Seventh Framework Programme FP7-2007-2013 (grant HEALTH-F2-2011-256986, PANACREAS), Spanish Ministerio de Economia y Competitividad (RD12/0036/0065 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III, cofunded by the Fondo Europeo de Desarrollo Regional of the European Union), Fondo de Investigación Sanitaria and European Commission (FIS-FEDER PS09/01915), Junta de Castilla y León (CSI052A11-2 and Biomedicine Project 2010-2011). CG was supported by the Ramón y Cajal Program from the Ministerio de Ciencia e Innovación of Spain. |
| Databáze: | OpenAIRE |
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