many yrs ago Al from Canada asked for a natural PI3K inhibitor--

[Lani]

now they have a lead on one which is "physiologic" ie, already present in one's body normally!

BT474 and SKBR3 are the two most commonly studied her2+ breast cancer cell lines--the first ER+, the second ER-

OPEN ACCESS: Phosphoinositide 3-kinase targeting by the β galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death
[Breast Cancer Research]
Introduction: Phosphoinositide 3-kinase (PI3K)-activated signalling has a critical role in the evolution of aggressive tumourigenesis and is therefore a prime target for anticancer therapy. Previously we have shown that the β galactoside binding protein (βGBP) cytokine, an antiproliferative molecule, induces functional inhibition of class 1A and class 1B PI3K. Here, we have investigated whether, by targeting PI3K, βGBP has therapeutic efficacy in aggressive breast cancer cells where strong mitogenic input is fuelled by overexpression of the ErbB2 (also known as HER/neu, for human epidermal growth factor receptor 2) oncoprotein receptor and have used immortalised ductal cells and non-aggressive mammary cancer cells, which express ErbB2 at low levels, as controls.
Methods: Aggressive BT474 and SKBR3 cancer cells where ErbB2 is overexpressed, MCF10A immortalised ductal cells and non-invasive MCF-7 cancer cells which express low levels of ErbB2, both in their naive state and when forced to mimic aggressive behaviour, were used. Class IA PI3K was immunoprecipitated and the conversion of phosphatidylinositol (4,5)-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) assessed by ELISA. The consequences of PI3K inhibition by βGBP were analysed at proliferation level, by extracellular signal-regulated kinase (ERK) activation, by akt gene expression and by apoptosis. Apoptosis was documented by changes in mitochondrial membrane potential, alteration of the plasma membrane, caspase 3 activation and DNA fragmentation. Phosphorylated and total ERK were measured by Western blot analysis and akt mRNA levels by Northern blot analysis. The results obtained with the BT474 and SKBR3 cells were validated in the MCF10A ductal cells and in non-invasive MCF-7 breast cancer cells forced into mimicking the in vitro behaviour of the BT474 and SKBR3 cells.
Results: In aggressive breast cancer cells, where mitogenic signalling is enforced by the ErbB2 oncoprotein receptor, functional inhibition of the catalytic activity of PI3K by the βGBP cytokine and loss of akt mRNA results in apoptotic death. A functional correlation between ERK and the kt gene was also found. The relationship between ERK, akt mRNA, PI3K and cell vulnerability to βGBP challenge was sustained both in mammary ductal cells forced to mimic an aggressive behaviour and in non-aggressive breast cancer cells undergoing an enforced shift into an aggressive phenotype.
Conclusions: βGBP, a newly discovered physiological inhibitor of PI3K, is a selective and potent inducer of apoptosis in aggressive breast cancer cells. Due to its physiological nature, which carries no chemotherapeutic disadvantages, βGBP has the potential to be safely tested in clinical trials.

[Ellie F]

Hi Lani
My onc told me a couple of months ago that in his opinion inhibiting this pathway was one of the most promising options for mets.
Does this research suggest any natural ways to boost production of this substance?
Ellie

[Lani]

it is an open access article--which means anyone has access to the full article

go to google put in breast cancer research

[Ellie F]

Thank you Lani. You are so diligent in keeping us up to date. We appreciate you
Ellie

[Rich66]

Meet everyone at Red lobster:


Results: 17

1.
Identification and characterization of multiple beta-glucan binding proteins in the Pacific oyster, Crassostrea gigas. (http://www.ncbi.nlm.nih.gov/pubmed/19995575?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=1)
Itoh N, Kamitaka R, Takahashi KG, Osada M.
Dev Comp Immunol. 2009 Dec 24. [Epub ahead of print]PMID: 19995575 [PubMed - as supplied by publisher]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=19995575&ordinalpos=1)


2.
Tregs utilize beta-galactoside-binding protein to transiently inhibit PI3K/p21ras activity of human CD8+ T cells to block their TCR-mediated ERK activity and proliferation. (http://www.ncbi.nlm.nih.gov/pubmed/19520156?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=2)
Baatar D, Olkhanud PB, Wells V, Indig FE, Mallucci L, Biragyn A.
Brain Behav Immun. 2009 Oct;23(7):1028-37. Epub 2009 Jun 9.PMID: 19520156 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=19520156&ordinalpos=2)


3.
Phosphoinositide 3-kinase targeting by the beta galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death. (http://www.ncbi.nlm.nih.gov/pubmed/19133120?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=3)
Wells V, Mallucci L.
Breast Cancer Res. 2009;11(1):R2. Epub 2009 Jan 8.PMID: 19133120 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=19133120&ordinalpos=3)Free article (http://www.ncbi.nlm.nih.gov/pubmed/19133120?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=3&log$=free)


4.
Identification and phylogenetic analysis on lipopolysaccharide and beta-1,3-glucan binding protein (LGBP) of kuruma shrimp Marsupenaeus japonicus. (http://www.ncbi.nlm.nih.gov/pubmed/18572243?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=4)
Lin YC, Vaseeharan B, Chen JC.
Dev Comp Immunol. 2008;32(11):1260-9. Epub 2008 Jun 4.PMID: 18572243 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=18572243&ordinalpos=4)


5.
Isolation, purification and characterization of beta-1,3-glucan binding protein from the plasma of marine mussel Perna viridis. (http://www.ncbi.nlm.nih.gov/pubmed/18420422?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=5)
Jayaraj SS, Thiagarajan R, Arumugam M, Mullainadhan P.
Fish Shellfish Immunol. 2008 Jun;24(6):715-25. Epub 2007 Dec 5.PMID: 18420422 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=18420422&ordinalpos=5)


6.
Functional inhibition of PI3K by the betaGBP molecule suppresses Ras-MAPK signalling to block cell proliferation. (http://www.ncbi.nlm.nih.gov/pubmed/17603562?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=6)
Wells V, Downward J, Mallucci L.
Oncogene. 2007 Dec 6;26(55):7709-14. Epub 2007 Jul 2.PMID: 17603562 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=17603562&ordinalpos=6)


7.
The effect of sodium alginate on the immune response of tiger shrimp via dietary administration: activity and gene transcription. (http://www.ncbi.nlm.nih.gov/pubmed/16684609?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=7)
Liu CH, Yeh SP, Kuo CM, Cheng W, Chou CH.
Fish Shellfish Immunol. 2006 Oct;21(4):442-52. Epub 2006 Mar 6.PMID: 16684609 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=16684609&ordinalpos=7)


8.
Changes in immune gene expression and resistance to bacterial infection in lobster (Homarus gammarus) post-larval stage VI following acute or chronic exposure to immune stimulating compounds. (http://www.ncbi.nlm.nih.gov/pubmed/16569431?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=8)
Hauton C, Brockton V, Smith VJ.
Mol Immunol. 2007 Jan;44(4):443-50. Epub 2006 Mar 29.PMID: 16569431 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=16569431&ordinalpos=8)


9.
Potential role of the antiproliferative cytokine beta-galactoside binding protein in cancer therapy. (http://www.ncbi.nlm.nih.gov/pubmed/16370387?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=9)
Mallucci L, Wells V.
Curr Opin Investig Drugs. 2005 Dec;6(12):1228-33. Review.PMID: 16370387 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=16370387&ordinalpos=9)


10.
Circumventing multidrug resistance in cancer by beta-galactoside binding protein, an antiproliferative cytokine. (http://www.ncbi.nlm.nih.gov/pubmed/15753355?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=10)
Ravatn R, Wells V, Nelson L, Vettori D, Mallucci L, Chin KV.
Cancer Res. 2005 Mar 1;65(5):1631-4.PMID: 15753355 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=15753355&ordinalpos=10)Free article (http://www.ncbi.nlm.nih.gov/pubmed/15753355?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=10&log$=free)


11.
Differential gene expression profile in hepatopancreas of WSSV-resistant shrimp (Penaeus japonicus) by suppression subtractive hybridization. (http://www.ncbi.nlm.nih.gov/pubmed/15450750?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=11)
Pan D, He N, Yang Z, Liu H, Xu X.
Dev Comp Immunol. 2005;29(2):103-12.PMID: 15450750 [PubMed - indexed for MEDLINE]Related articles (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=15450750&ordinalpos=11)


12.
Real-time PCR quantification of the in vitro effects of crustacean immunostimulants on gene expression in lobster (Homarus gammarus) granular haemocytes. (http://www.ncbi.nlm.nih.gov/pubmed/15325521?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed _ResultsPanel.Pubmed_RVDocSum&ordinalpos=12)
Hauton C, Hammond JA, Smith VJ.
Dev Comp Immunol. 2005;29(1):33-42.PMID: 15325521 [PubMed - indexed for MEDLINE]

[Ellie F]

OK Rich, this is going to keep me REALLY busy!!
Ellie

[Lien]

See, I knew there was a reason why I like shellfish! Wonder if Dutch shrimps offer the same. They are gooood!

[Lani]

the link
http://breast-cancer-research.com/content/11/1/R2

[Chelee]

Ellie, I started laughing at your comment to Rich...I was thinking the exact same thing! lol (Although...I bet it will take me much longer then you to digest all this info.) I have to read it a few times to understand it all at times. lol :) Just being honest!

Thanks Rich! ;)

Chelee

[Ellie F]

Chelee
I keep reading it but still not sure I fully understand it. Maybe it's the chemo that's done it to me!

Does it imply that eating seafood eg shrimps, lobster etc may provide natural sources of the substance that inhibits the P13k pathway or have I totally got this wrong ?

Ellie

[Ellie F]

Ok folks. I really really need some help understanding this!! We have lots of scientifically gifted folk on this site so am hoping for a (reasonably) simple explanation.

I now understand the biology of the P13k pathway (well at least a little) but wondering whether this substance needs to be IV or ingested to be effective??

I have trawled for clinical trials but have drawn a blank. Does this mean that it is so new that nobody has sorted one out OR would there not be enough profit for drug companies to develop this??

Any thoughts very much appreciated.
Ellie

[Lani]

from the article:
Secreted by CD4+ and CD8+ -activated T cells [31] and by somatic cells [30], endogenous βGBP controls cell cycle entry and S/G2 traverse [30]. In its recombinant form βGBP

Thus they could try to increase the number of CD4+ and CD8+ activated T cells secreting beta GBP or provide more in its "recombinant form"--made by bacteria or in tobacco plants via gene therapy means.

This article is about a year old...it comes out of England where they are trying to find cheaper treatments as otherwise NICE won't approve them, so maybe someone/somewhere is starting/intending to start a clinical trial. Lots to figure out about how best to increase production of this natural substance, whether it needs to be raised continuously or intermittently, optimal level, how long to treat(perhaps a one time dose if appropriately targeted as it causes massive apoptosis), whether such massive apoptosis is prudent or whether lots of cell debris might overwhelm the kidneys...

Lots of work to be done, but hopeful!

[Ellie F]

Thanks Lani
What you say is cetainly true about NICE hence we can't get tykerb except in trials.
Certainly if one comes on line in England I would be very interested. My onc, just back from research is very ON targeting this pathway as he feels it would be very effective.
Ellie