Universidad de Granada Digibug
 

Repositorio Institucional de la Universidad de Granada >
1.-Investigación >
Departamentos, Grupos de Investigación e Institutos >
Departamento de Química Analítica >
DQA - Artículos >

Please use this identifier to cite or link to this item: http://hdl.handle.net/10481/31177

Title: Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin™) in HER2-overexpressing breast cancer cells
Authors: Menéndez, Javier A.
Vázquez-Martín, Alejandro
Colomer, Ramón
Brunet, Joan
Carrasco-Pancorbo, Alegría
García-Villalba, Rocío
Fernández Gutiérrez, Alberto
Segura Carretero, Antonio
Issue Date: 2007
Abstract: [Background] A low incidence of breast cancer in the Mediterranean basin suggests that a high consumption of Extra Virgin Olive Oil (EVOO) might confer this benefit. While the anti-HER2 oncogene effects of the main ω-9 fatty acid present in EVOO triacylglycerols (i.e., oleic acid) have been recently described, the anti-breast cancer activities of EVOO non-glyceridic constituents -which consist of at least 30 phenolic compounds-, remained to be evaluated. [Methods] Semi-preparative HPLC was used to isolate EVOO polyphenols (i.e., tyrosol, hydroxytyrosol, oleuropein). Both the anti-proliferative and the pro-apoptotic effects of EVOO phenolics were evaluated by using MTT-based quantification of metabolically viable cells and ELISA-based detection of histone-associated DNA fragments, respectively. The nature of the interaction between oleuropein aglycone and the anti-HER2 monoclonal antibody trastuzumab (Herceptin™) was mathematically evaluated by the dose-oriented isobologram technique. HER2-specific ELISAs were employed to quantitatively assess both the basal cleavage of the HER2 extracellular domain (ECD) and the expression level of total HER2. The activation status of HER2 was evaluated by immunoblotting procedures using a monoclonal antibody specifically recognizing the tyrosine phosphorylated (Phosphor-Tyr1248) form of HER2. [Results] Among EVOO polyphenols tested, oleuropein aglycone was the most potent EVOO phenolic in decreasing breast cancer cell viability. HER2 gene-amplified SKBR3 cells were ~5-times more sensitive to oleuropein aglycone than HER2-negative MCF-7 cells. Retroviral infection of the HER2 oncogene in MCF-7 cells resulted in a "SKBR3-assimilated" phenotype of hypersensitivity to oleuropein aglycone. An up to 50-fold increase in the efficacy of trastuzumab occurred in the presence of oleuropein aglycone. A preclinical model of acquired autoresistance to trastuzumab (SKBR3/Tzb100 cells) completely recovered trastuzumab sensitivity (> 1,000-fold sensitization) when co-cultured in the presence of oleuropein aglycone. Indeed, the nature of the interaction between oleuropein aglycone and trastuzumab was found to be strongly synergistic in Tzb-resistant SKBR3/Tzb100 cells. Mechanistically, oleuropein aglycone treatment significantly reduced HER2 ECD cleavage and subsequent HER2 auto-phosphorylation, while it dramatically enhanced Tzb-induced down-regulation of HER2 expression. [Conclusion] Olive oil's bitter principle (i.e., oleuropein aglycone) is among the first examples of how selected nutrients from an EVOO-rich "Mediterranean diet" directly regulate HER2-driven breast cancer disease.
Sponsorship: JAM is the recipient of a Basic, Clinical and Translational Research Award (BCTR0600894) from the Susan G. Komen Breast Cancer Foundation (Texas, USA). This work was also supported by the Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria -FIS-, Spain, Grants CP05-00090 and PI06-0778 to JAM, and Grant RD06-0020-0028 to JAM, RC and JB).
Publisher: Biomed Central
Keywords: Antibodies
Monoclonal
Breast neoplasms
Cell line
Drug resistance
Genes
Plant extracts
Plant oils
Pyrans
Olive oil
Trastuzumab
Oleuropein
URI: http://hdl.handle.net/10481/31177
ISSN: 1471-2407
Citation: Menéndez, J.A.; et al. Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin™) in HER2-overexpressing breast cancer cells. BMC Cancer, 7: 80 (2007). [http://hdl.handle.net/10481/31177]
Appears in Collections:DQA - Artículos

Files in This Item:

File Description SizeFormat
Menendez_Herceptin.pdf975.03 kBAdobe PDFView/Open
Recommend this item

This item is licensed under a Creative Commons License
Creative Commons

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

 

Valid XHTML 1.0! OpenAire compliant DSpace Software Copyright © 2002-2007 MIT and Hewlett-Packard - Feedback

© Universidad de Granada