[chrisy]

Hi all you propellerheads and wannabes,

I posted another thread with this question and we had some interesting discussions but mostly not addressing my basic question! I'm going to break a rule here and post article texts (I posted the links on the other thread "Olive oil and Her2 downregulation - question for the propellerheads").

I'm interested in some educated interpretations of how the 3 studies below would relate to use of Trastuzumab-MCC-DM1, which is Herceptin with a toxin attached. The Herceptin is used as a targeting mechanism, but the TOXIN kills the cancer cells. My thinking is that you would want to avoid substances that would work competitively with Herceptin, because you want the max toxin into the cells. So where various components of EVOO could work synergistically with Herceptin, they might actually work against the action of the DM1.

These 3 studies from our friend Menendez look at two components. I think it seems ALA might be contraindicated with DM1, but oleuropein aglycone would be synergistic. But then again, remember that I'm an accountant not a biologist so since the articles don't mention debits or credits, I'm a bit out of my element.

I know we're just talking about petri dishes, here, but what do you think?

Article 1 on ALA:
Mediterranean diet, olive oil and cancer. Clin Transl Oncol. 2006 Jan;8(1):15-21.

<!--AuthorList-->Colomer R, Menéndez JA.
Medical Oncology, Institut Catala d'Oncologia, Hospital de Girona Dr. Josep Trueta, Girona, Spain. rcolomer@ico.scs.es
Olive oil is an integral ingredient of the "Mediterranean diet" and accumulating evidence suggests that it may have a potential role in lowering the risk of several types of cancers. The mechanisms by which the cancer-preventing effects of olive oil can be performed, however, are not known. We recently hypothesized that a novel molecular explanation concerning the anti-cancer actions of olive oil may relate to the ability of its monounsaturated fatty acid (MUFA) oleic acid (OA; 18:1n-9) to specifically regulate cancer-related oncogenes. Supporting our hypothesis, exogenous supplementation of cultured breast cancer cells with physiological concentrations of OA was found to suppress the overexpression of HER2 (Her-2/neu, erbB-2), a well-characterized oncogene playing a key role in the etiology, progression and response to chemotherapy and endocrine therapy in approximately 20% of breast carcinomas. OA treatment was also found to synergistically enhance the efficacy of trastuzumab, a humanized monoclonal antibody binding with high affinity to the ectodomain (ECD) of the Her2-coded p185(HER2) oncoprotein. Moreover, OA exposure significantly diminished the proteolytic cleavage of the ECD of HER2 and, consequently, its activation status, a crucial molecular event that determines both the aggressive behavior and the response to trastuzumab of Her2-overexpressing breast carcinomas. Our most recent findings further reveal that OA exposure may suppresses HER2 at the transcriptional level by up-regulating the expression of the Ets protein PEA3 -a DNA-binding protein that specifically blocks HER2 promoter activity- in breast, ovarian and stomach cancer cell lines. This anti-HER2 property of OA offers a previously unrecognized molecular mechanism by which olive oil may regulate the malignant behavior of cancer cells. From a clinical perspective, it could provide an effective means of influencing the outcome of Her-2/neu-overexpressing human carcinomas with poor prognosis. Indeed, OA-induced transcriptional repression of HER2 oncogene may represent a novel genomic explanation linking "Mediterranean diet", olive oil and cancer as it seems to equally operate in various types of Her-2/neu-related carcinomas.
PMID: 16632435 [PubMed - indexed for MEDLINE]


<dl class="commcorr"><dt>Article 2 on ALA
</dt><dt>Comment in:</dt><dd>Ann Oncol. 2005 Mar;16(3):339-40. </dd></dl>Oleic acid, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu (erbB-2) expression and synergistically enhances the growth inhibitory effects of trastuzumab (Herceptin) in breast cancer cells with Her-2/neu oncogene amplification.

<!--AuthorList-->Menendez JA, Vellon L, Colomer R, Lupu R.
Department of Medicine, Breast Cancer Translational Research Laboratory, Evanston Northwestern Healthcare Research Institute, 1001 University Place, Evanston, IL 60201, USA.
BACKGROUND: The relationship between the intake of olive oil, the richest dietary source of the monounsaturated fatty acid oleic acid (OA; 18:1n-9), and breast cancer risk and progression has become a controversial issue. Moreover, it has been suggested that the protective effects of olive oil against breast cancer may be due to some other components of the oil rather than to a direct effect of OA. METHODS: Using flow cytometry, western blotting, immunofluorescence microscopy, metabolic status (MTT), soft-agar colony formation, enzymatic in situ labeling of apoptosis-induced DNA double-strand breaks (TUNEL assay analyses), and caspase-3-dependent poly-ADP ribose polymerase (PARP) cleavage assays, we characterized the effects of exogenous supplementation with OA on the expression of Her-2/neu oncogene, which plays an active role in breast cancer etiology and progression. In addition, we investigated the effects of OA on the efficacy of trastuzumab (Herceptin), a humanized monoclonal antibody binding with high affinity to the ectodomain of the Her-2/neu-coded p185(Her-2/neu) oncoprotein. To study these issues we used BT-474 and SKBr-3 breast cancer cells, which naturally exhibit amplification of the Her-2/neu oncogene. RESULTS: Flow cytometric analyses demonstrated a dramatic (up to 46%) reduction of cell surface-associated p185(Her-2/neu) following treatment of the Her-2/neu-overexpressors BT-474 and SK-Br3 with OA. Indeed, this effect was comparable to that found following exposure to optimal concentrations of trastuzumab (up to 48% reduction with 20 microg/ml trastuzumab). Remarkably, the concurrent exposure to OA and suboptimal concentrations of trastuzumab (5 microg/ml) synergistically down-regulated Her-2/neu expression, as determined by flow cytometry (up to 70% reduction), immunoblotting, and immunofluorescence microscopy studies. The nature of the cytotoxic interaction between OA and trastuzumab revealed a strong synergism, as assessed by MTT-based cell viability and anchorage-independent soft-agar colony formation assays. Moreover, OA co-exposure synergistically enhanced trastuzumab efficacy towards Her-2/neu overexpressors by promoting DNA fragmentation associated with apoptotic cell death, as confirmed by TUNEL and caspase-3-dependent PARP cleavage. In addition, treatment with OA and trastuzumab dramatically increased both the expression and the nuclear accumulation of p27(Kip1), a cyclin-dependent kinase inhibitor playing a key role in the onset and progression of Her-2/neu-related breast cancer. Finally, OA co-exposure significantly enhanced the ability of trastuzumab to inhibit signaling pathways downstream of Her-2/neu, including phosphoproteins such as AKT and MAPK. CONCLUSIONS: These findings demonstrate that OA, the main monounsaturated fatty acid of olive oil, suppresses Her-2/neu overexpression, which, in turn, interacts synergistically with anti-Her-2/neu immunotherapy by promoting apoptotic cell death of breast cancer cells with Her-2/neu oncogene amplification. This previously unrecognized property of OA offers a novel molecular mechanism by which individual fatty acids may regulate the malignant behavior of breast cancer cells and therefore be helpful in the design of future epidemiological studies and, eventually, dietary counseling.
PMID: 15642702 [PubMed - indexed for MEDLINE]


Article 3, on oleuropein aglycone:
<dl class="PubmedArticle"><dd class="abstract">Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin) in HER2-overexpressing breast cancer cells.BMC Cancer. 2007 May 9;7:80

<!--AuthorList-->Menendez JA, Vazquez-Martin A, Colomer R, Brunet J, Carrasco-Pancorbo A, Garcia-Villalba R, Fernandez-Gutierrez A, Segura-Carretero A.
Catalan Institute of Oncology (ICO)-Health Services Division of Catalonia, Spain. jmenendez@ico.scs.es
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 omega-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.
PMID: 17490486 [PubMed - indexed for MEDLINE]
PMCID: PMC1878493
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