Lani? RB? Becky? HELP! on EVOO question

[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
</dd></dl>

[Becky]

Dear Chris

It seems to me that if you were just on Herceptin, one would want the olive oil high in the diet because both Herceptin and some component(s) of EVOO bind to the extra cellular domain of Her2+ bc cells and then encourage apoptosis (cell death) versus reproduction. That is a good thing.

However, in the case of MCC-DM1, you might want as many of the tagged Herceptin molecules to attach to the extra cellular domain since it has the toxin attached to it. This ensures that more bc cells should be killed and since the half life of Herceptin is still about 25 days, it should keep killing if the toxin stays around that long.

I think the difference comes into play if EVOO also binds to other Her family sites besides the Her2 site, then it might be mega beneficial but I have never seen any other studies except ones like the one you attached.

It would seem to me that I wouldn't over indulge the EVOO. But then again, what does that mean. For example, if one ate it as salad dressing or had a tablespoon per day, is that even enough to have a therapeutic effect at all? We really don't know if we have to drink a cup per day or more to get the kind of effect in the human body (once it hits the stomach and finally hits the bloodstream) as they do in these petri dish studies. If you are having EVOO salad dressing, I think it would be just fine (and good for your heart) to go about life business as usual. Since drinking it off the spoon isn't really "natural" like using it in cooking, why do that while in this trial? Also, don't take Olive leaf supplements as they are oleuropein but otherwise, I wouldn't cut EVOO completely out of the diet unless you are using it so excessively.

Any little bit that is "left over" to bind to the ECD would be negliable in a normal diet (but may be chemoprotective over a lifetime on the Med diet).

That's my humble opinion and I'm stickin' to it!

Rock on.

[lilyecuadorian]

I like your conclusion Becky ......normal EVOO is OK now ...when we are on this trial ...DM1 ...really, Ignorance is my worst evil enemy ....

[chrisy]

Yeah, Becky, I agree with your thinking, that the key to T-Dm1 would be to get the maximum number of molecules binding to the ECD. Not that I'm trying to get you unstuck from your story...

But that's where I think it gets complicated with the oleuropein - because part of it's action seems to be to DECREASE cleavage of the ECD. Doesn't that mean less ECD disconnected from the cell and MORE available for binding to the Herceptin? Of course, the other theorized mechanism is downregulation of Her2. It is interesting to me though that reversal of Herceptin resistance was so significant - which would seem to be a good thing for T-DM1.

Of course, as you say, none of this has any clinical relevance in terms of what it would do in humans, how much would it take, etc. Glad there's no reason to start chugging EVOO!

Thanks for your response Becky, I can always count on you!

"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."

[R.B.]

Chrisy,

I wish I could help. I just do not anything much about the area you are looking at.

I tend to take a broader viewpoint.

Trials suggest that improving fats intake eg less omega six, more long chain omega three reduces the risk of BC.

Certain agents in olive oil may have risk reduction properties.

Olive oil and the omega 9 it contains reduces the amount of omega six in in the cells for those on average western diets. This has a number of effects on cell function.

It is highly complex, much is not know, and I struggle with it.

Fats and olive oil will be acting in a myriad of ways. fats are fundamental and the body is unimaginably complex.

At the end of the day a limited number of trials suggest that a better long chain omega3 lower omega 6 profile / better diet can reduce your BC risk by up to 70% is not a possibility it seems to me that should me lightly set aside.

RB

[runtolive]

i would not mess with alternative ideas of treatment until u find out if the tras-dm1 is working or failing.. i dont expect it to fail.. but doing anything out of the ordinary. taking enhancers,inhibitors etc that may alter the dynamics of this drug would be a huge mistake.. dont do it..

this drug has outperformed all the herceptin data head to head.. and will likely keep u alive far longer than herceptin therapy did. remember.. HERCEPTIN. has failed.. this treatment is unfortunately a last resort.. without it, we get poisoned by taxotere, and xeloda again

[chrisy]

Hey run,

don't get me wrong...

We make changes in our dietary habits based on whatever evidence is out there. Things like eating "healthy" diets such as the mediterranean diet. Many/most of these lifestyle changes fit into the category of "couldn't hurt, and MAY tip the scales a bit in my favor". The fact that there is actually good research on WHY this type of diet may fight cancer, Her2+ cancer in particular makes it even more likely that people on this board will make such choices.

In looking at T-DM1's mechanism of action, it raised a question for me whether that type of diet might be contraindicated. Seems unlikely that a normal healthy diet would be, but I had to ask.

That's not looking at an "alternative treatment", just raising the question that evidence suggesting dietary synergy with Herceptin might suggest the opposite with this new therapy. Which I actually expect to work quite well - and I want to be sure I stay out of it's way so it can do it's work!

[runtolive]

i am just saying that any significant changes to your routine.. eg.. only eating seafood..or a non fat diet.. etc.. some of those changes may be counter productive.

herceptin itself is only a static drug.. meaning it can hold the cancer at bay for awhile.. some patients respond better than others. but adding the maytansinoid toxin actually makes it a "" CIDAL"' DRUG.. which means it kills the cancer cells..

i was not familiar with the EVOO diet considerations,, but i do know that the drug you are taking has been working pretty well for the ladies on this board who take it. and i suspect it will work well for you.. i have seen all the data, and listened to genentech about how happy, practically giddy on their conference calls when they mention this drug. its only a matter of time until the drug gets approved. possibly 2 years from now.. hopefully all the ladies on this board who relapse can ask their doctors about it and if qualified, get enrolled in this study asap.. the ladies on this trial are working to save potentially hundred of thousand of lives. stay strong ladies..

run to live.

[SoCalGal]

Just wanted to say that I am very hungry after reading this link...
Flori

[chrisy]

Then I will be happy. Even more so if that run DMC herceptin goes 'cidal on that cancer.