We need a natural PI3K inhibitor, Becky

[al from Canada]

Good morning folks,

I've posted about this many times before and would like to find an active PI3K inhibitor. It seems this expression has everything to do with the up-regulation of HER2 and many, many other anti-apoptosis factors and cell proliferation responses. There is considerable research with two specific PI3K down regulators; LY294002 and wortmannin, the latter being extracted from some kind of fungus. Recently, another protein has been linked with PI3K up-regulation, (abstract below).

Does our resident micro-biologist, or anyone else for that matter, have any suggestions?

Regards,
Al

Survivin, a member of the inhibitor of apoptosis protein family, is widely expressed in a variety of human cancer tissues. Survivin inhibits activation of caspases, and its overexpression can lead to resistance to apoptotic stimuli. In this study, survivin protein expression was assessed by immunohistochemical staining of 195 invasive breast cancer specimens. Overall, 79.5% of the tumors were positive for survivin. The expression of epidermal growth factor receptor (EGFR) family, human epidermal growth factor receptor 2 (HER2) and EGFR, was also examined in 53 cases, and consequently, it was indicated that survivin positivity might be correlated with the coexpression of HER2 and EGFR. To clarify the regulatory mechanism of survivin expression in breast cancer cells, the effect of HER2 and/or EGFR expression on the survivin levels was examined. It was revealed that the survivin protein level was up-regulated by the coexpression of HER2 and EGFR, leading to the increased resistance against etoposide-induced apoptosis in breast cancer cells. Conversely, survivin levels and apoptosis resistance were decreased when cells were treated with HER2-specific inhibitor, Herceptin. Although Herceptin could down-regulate both phosphatidylinositol 3-kinase (PI3K)/AKT signal and mitogen-activated protein/extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signal in HER2-positive breast cancer cells, PI3K-specific inhibitor but not MEK1-specific inhibitor could decrease the survivin levels. The present study clarified the regulatory mechanism of HER2 in the expression of survivin protein in breast cancer cells.

[RobinP]

Hi Al,
Sounds like you're pTEN deficient?





Ann Oncol. 2004 Oct;15(10):1510-6. Related Articles, Links [img]/entrez/query/egifs/http:--highwire.stanford.edu-icons-externalservices-pubmed-free-annonc-free.gif[/img]
Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway.

DeGraffenried LA, Fulcher L, Friedrichs WE, Grunwald V, Ray RB, Hidalgo M.

University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

The PTEN protein is a lipid phosphatase with putative tumor suppressing abilities, including inhibition of the PI3K/Akt signaling pathway. Inactivating mutations or deletions of the PTEN gene, which result in hyper-activation of the PI3K/Akt signaling pathway, are increasingly being reported in human malignancies, including breast cancer, and have been related to features of poor prognosis and resistance to chemotherapy and hormone therapy. Prior studies in different tumor models have shown that, under conditions of PTEN deficiency, the PI3K/Akt signaling pathway becomes a fundamental proliferative and survival pathway, and that pharmacological inhibition of this pathway results in tumor growth inhibition. This study aimed to explore further this hypothesis in breast cancer cells. To this end, we have determined the growth response to inhibition of the PI3K/Akt signaling pathway in a series of breast cancer cell lines with different PTEN levels. The PTEN-negative cell line displayed greater sensitivity to the growth inhibitory effects of the PI3K inhibitor, LY294002 and rapamycin, an inhibitor of the PI3K/Akt downstream mediator mTOR, compared with the PTEN-positive cell lines. To determine whether or not these differences in response are specifically due to effects of PTEN, we developed a series of cell lines with reduced PTEN protein expression compared with the parental cell line. These reduced PTEN cells demonstrated an increased sensitivity to the anti-proliferative effects induced by LY294002 and rapamycin compared with the parental cells, which corresponded to alterations in cell cycle response. These findings indicate that inhibitors of mTOR, some of which are already in clinical development (CCI-779, an ester of rapamycin), have the potential to be effective in the treatment of breast cancer patients with PTEN-negative tumors and should be evaluated in this setting.

PMID: 15367412 [PubMed - indexed for MEDLINE

[Becky]

Robin was good to remind me about Pten activation (of which beta glucans found primarily in maitake mushrooms help activate if you have an inactive form). I know that you mentioned once that Linda does take these. The problem is what is enough for an effect versus too much that can interfer with other supplements. I take six 545mg capsules of dried maitake a day.


Now for P13K inhibitors. One that is common and available is selenium (in most multi's and supplements as sodium selenate). It is NOT the selenium that is the inhibitor. It is that excess selenium is converted in the body as methylselanol (a more water soluble version that can be eliminated by the urinary tract). This version is a known P13K inhibitor and this version is also highly TOXIC. I write this in bold for everyone reading this to see, understand and continue to read this post with thoughfulness. Selenium in high doses is toxic, toxic, toxic (since excess is converted to this toxic form). A little too much isn't going to do anything but what exactly is a little too much (hence, my initial advice is to take supplementation to what is consider 100% of the RDA and then focus on food sources initially).

Foods that are a good source of selenium include fish (especially shellfish), red meat, grains (especially wheat germ which is easy to sprinkle on your cereal), eggs, chicken, liver and garlic. Brewer's yeast is also high in selenium.

Al - I will continue to look for you as some "experimentals" out there are actually vitamins under an experimental number.

Stay tuned

Becky

[al from Canada]

Good thought Robin, the problem with many of these studies is that they don't address the other multitude of interactions that may cause PTEN inhibition or PI3K over-expression for that matter...and we know that cancer has many x-talk fail-safes. I mentioned PI3K because it keeps cropping-up over and over and over.....
Thanks for your info, Becky. Doesn't sound like selenium is the supplement of choice. We'll keep digging...

Here is a link to an excellent summary of PI3K actions and if you notice on the chart, IP6 is involved but it looks like it is downstreamstream, I'm not a biology person.
Misregulation of inositol signalling pathways has been implicated in a variety of diseases, including hypertension, diabetes and neuronal disorders, prompting the developmt of pharmacological agents that re-establish normal inositol signalling....inhibitors of PI3K are candidates for therapeutic agents for cancers and related metabolic diseases."


http://www.nyu.edu/classes/ytchang/r...d%20review.pdf

Regards,
Al

[Becky]

Okay - here's another good one and this one is very, very interesting. Vanadium - like selenium is toxic but food sources include cereals especially buckwheat and oats, green beans, olive and peanut oils, carrots, cabbage, corn, parsley, garlic and sunflower seeds.

The interesting thing is that researchers are also looking at it in treating diabetes because it controls insulin resistance and the insulin pathway as well (scientific name of vanadium is sodium vanadate). Now - if you have read my posts from way back, I used think that besides Her 2 and ER/PR receptors on breast cancer cells that there could be insulin receptors. I have given up on this theory because they would have found them by now AND that insulin is a HUGE molecule - just enormous. But... it does enter into the same P13K pathway and the same inhibitors are being looked at for diabetes. (I just found this interesting is all...).

I will keep up the look and at work (since it is a chemical company that I work for).

Becky

[RobinP]

Al, what you are looking for is both effective and simplistic at inducing apoptosis in breast cancer cells via of IGF-I inhibition which leads to PI3K inactivation, its called vit. D. I brought up the use of vit D a few weeks ago and it's use by Dr. DiGiovanna in new clinical trails: trails-http://www.bcrfcure.org/rese_meet_digiovanna.html.



Interactions of vitamin D analogues with downstream effectors of insulin-like growth factor 1 (IGF-I) signalling

LC Lowe, C Mørk Hansen & KW Colston

Oncology, Gastroenterology Endocrinology and Metabolism, St Georges Hospital Medical School, London, UK.

Raised levels of IGF-I have been associated with risk of developing several cancers including breast carcinoma. In addition to promoting mitogenesis in breast cancer cells, a number of observations suggest a role for inhibition of apoptosis by IGF-I receptor activation. Ligand binding to IGF-IR leads to activation of both the phosphoinositide-3'-kinase (PI3K) and the Ras/Raf/MAPKinase pathways. Deprivation of serum growth factors induces apoptosis in MCF-7 breast cancer cells and this effect can be abrogated by supplementation of serum free medium (SFM) with IGF-I via activation of the PI3K pathway. Co-treatment of MCF-7 cells with the vitamin D analogue EB1089 can attenuate the anti-apoptotic actions of IGF-I. To investigate the mechanism(s) by which EB1089 prevents IGF-I-mediated cell survival we compared interactions between this analogue and IGF-I in parental MCF-7 cells and a stable subclone (MCF-7/VDR) that is resistant to the growth inhibitory and apoptosis inducing effects of vitamin D. IGF-I promoted survival of parental and MCF-7/VDR cells in SFM such that >90% viability was obtained with cultures incubated with 4nM IGF-I for 4 days. Co-treatment with 100nM EB1089 attenuated the effects of IGF-I in parental but not MCF-7/VDR cells. Attenuation of IGF-I effects in parental cells was accompanied by a decrease in IGF-I-mediated PI3K activation (as assessed by levels of phosphorylated Akt). Using phosphospecific antibodies we obtained evidence that EB1089 treatment of parental cells promotes the pro-apoptotic p38 MAPK but not the ERK/MAPK pathway. In addition MCF-7/VDR basally contain a higher proportion of phosphorylated to total Akt, compared with parental MCF-7 cells. This may in part account for their resistance to vitamin D analogues. However, both cell lines are sensitive to the PI3K inhibitor wortmannin suggesting that even in the presence of a higher proportion of phosphorylated Akt, MCF-7/VDR cell death can be induced by blocking this cell survival pathway.

This research is funded by The Breast Cancer Research Trust and the World Cancer Research Fund.

[jojo]

Whoa!... This just goes over my head -- and I have a college dregree (though not in science)! I am just amazed at the extensive research you keep coming up with. It is hard to catch up with you guys! I REALLY appreciate your teamwork. I love the feeling of being in a large & caring team, especially when it comes to life-threatening issues!

Keep up the good job! :-)