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TNBC / testing strategies in a NED situation

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(@j)
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Posted by: @rosed

@j I didn't know that about CA.  Good!    Thanks!!!! 😊

I knew it was a chelator but didn't know it was chelating iron. Nice!

 


   
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(@j)
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" There were two unexpected findings: 1) a strong induction of CYPs involved in activation of fatty acids (CYP4), and in inactivation of calcitriol (CYP24A1) and retinoic acid (CYP26A1); and 2) a marked down-regulation of FOS, FRA1, and JUN, known tethering partners of ERβ. ERβ is expressed in 20 to 30% of TNBCs and is being evaluated as a target for treating TNBC. We used ERβ+ TNBC patient-derived xenografts in mice and found that the ERβ agonist LY500703 had no effect on growth or proliferation. Expression of CYPs was confirmed by immunohistochemistry in formalin-fixed and paraffin-embedded (FFPE) TNBC. In TNBC cell lines, the CYP4Z1-catalyzed fatty acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) increased proliferation, while calcitriol decreased proliferation but only after inhibition of CYP24A1. We conclude that CYP-mediated pathways can be drivers of TNBC but that ERβ is unlikely to be a tumor suppressor because the absence of its main tethering partners renders ERβ functionless on genes involved in proliferation and inflammation."

also, see attachment, calcitriol (the activated form of vitamin D3) and ketoconazole show strong inhibition

 

 

both are very cheap drugs btw. quite remarkable.

 


   
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(@j)
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Quick note, I've updated the diagram and added the above-mentioned combo and a few other additions (chrysin)

https://synergiesforcancertreatments.blogspot.com/p/triple-negative-breast-cancer-tnbc.html


   
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(@j)
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@rosaleend

Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin‑resistant human epidermal growth factor receptor 2‑positive breast cancer

https://www.spandidos-publications.com/10.3892/ol.2021.12927/abstract


   
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(@chris48)
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Posted by: @rosed

@chris48 Cancer treatment is so miserable ..... hard to even think of ice cold showers/baths 😬 .... that's why the notion of a 3 minute chamber sounded more manageable to me.  I can't say it sounds all that much more appealing though. I will continue to investigate..... I will let you know if I decide to try.  My immune system is still low from all my ACT/Carbo chemo and now they want to dump more in to me. Plenty of decisions upcoming. All my best to Bianca.

Yes, ice baths are very painful and even a cold shower is very hard if you are not used to it. I did cryotherapy twice and it was way easier to do. There was no pain at all, not even an elevated heart rate. -120°C sounds brutal, but in those chambers it actually is absolutely doable for anyone. But the thing is, that according to the studies even the breathing technique alone did alter the immune function. That is where I saw the most potential. It is also the breathing that changed the blood pH dramatically. Therefore I thought it might be of use for an alkalization strategy.

Anyway, there are so many routes and we can't take them all at once. I wish you best of luck!

 


   
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(@chris48)
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https://journals.sagepub.com/doi/full/10.1177/1534735420975861?fbclid=IwAR1ddFoNtKXRZFvPZWZwo4m4jpn7gSdYn1JCuFcpz9Zuwa3raxdBC28a1Ak&

"This paper collates pre-clinical results, first to determine the tumor’s mechanisms of growth and then to source natural substances that could potentially suppress those mechanisms. The results from in vivo and in vitro studies of TNBC were combined first to select 10 primary mechanisms (Hypoxia-inducible factor 1α, Hedgehog, MAPK, MTAP, NF-κ B, Notch, P13K, STAT3, and Wnt signaling pathways plus p53 and POL2A gene expression) that promote TNBC growth, and second to propose a treatment array of 21 natural compounds that suppress laboratory models of TNBC via these mechanisms."

I found that one really interesting. What are your thoughts on this study?


   
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(@j)
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@chris48 Very interesting approach, one weakness of course is the selection of what they call the 10 primary mechanisms. It's not that easy to define as one study I posted above shows:

"In the present study, the limited effect of ERβ expression in TNBC suggests caution in extrapolation from TNBC cell lines to human TNBC samples. The MDA-MB-231 cell line was isolated from a patient with invasive ductal carcinoma (IDC) which expressed ERα (48). All of the other TNBC cell lines were also derived from breast cancers that were not originally TNBC (49). These cell lines do have in common with TNBC the lack of expression of ER, PR, or HER2 but that does not make them true representatives of TNBC. This difference between the TNBC cell lines and TNBC in patient samples may explain why other pathways previously reported to be involved in TNBC cell lines (GPNMP, EGFR, Notch 1–3, mTOR, AKT 1 and 2, TGFβ, activin receptor, SMAD 7) were all down-regulated in RNA-seq of the TNBC patient samples."

It doesn't address pH, lactic acid, etc. It doesn't make use of synergistic combinations which in my view is of utmost importance. Look at the inhibition of calcitriol + ketoconazole {ref}, KCZ alone almost does nothing, calcitriol alone seems to induce, whereas both together cause remarkable inhibition. 

But the result help to confirm or validate the use of certain substances!

 

 

 


   
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(@j)
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Posted by: @j

Posted by: @j

@medline what do you think of the use of apigenin in TNBC?

@aml

 

I think it's OK, but I'd use it in specific combinations such as with metformin.

 


   
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(@j)
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Posted by: @j

@chris48 Very interesting approach, one weakness of course is the selection of what they call the 10 primary mechanisms. It's not that easy to define as one study I posted above shows:

"In the present study, the limited effect of ERβ expression in TNBC suggests caution in extrapolation from TNBC cell lines to human TNBC samples. The MDA-MB-231 cell line was isolated from a patient with invasive ductal carcinoma (IDC) which expressed ERα (48). All of the other TNBC cell lines were also derived from breast cancers that were not originally TNBC (49). These cell lines do have in common with TNBC the lack of expression of ER, PR, or HER2 but that does not make them true representatives of TNBC. This difference between the TNBC cell lines and TNBC in patient samples may explain why other pathways previously reported to be involved in TNBC cell lines (GPNMP, EGFR, Notch 1–3, mTOR, AKT 1 and 2, TGFβ, activin receptor, SMAD 7) were all down-regulated in RNA-seq of the TNBC patient samples."

It doesn't address pH, lactic acid, etc. It doesn't make use of synergistic combinations which in my view is of utmost importance. Look at the inhibition of calcitriol + ketoconazole {ref}, KCZ alone almost does nothing, calcitriol alone seems to induce, whereas both together cause remarkable inhibition. 

But the result help to confirm or validate the use of certain substances!

 

 

 

Btw, here are the substances they chose:  The 7 substances of our final array are Curcumin, Burdock, Garlic, Fisetin, Korean Ginseng, Sulforaphane and Quercetin.

 

 


   
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(@j)
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Posted by: @j

Posted by: @j

@chris48 Very interesting approach, one weakness of course is the selection of what they call the 10 primary mechanisms. It's not that easy to define as one study I posted above shows:

"In the present study, the limited effect of ERβ expression in TNBC suggests caution in extrapolation from TNBC cell lines to human TNBC samples. The MDA-MB-231 cell line was isolated from a patient with invasive ductal carcinoma (IDC) which expressed ERα (48). All of the other TNBC cell lines were also derived from breast cancers that were not originally TNBC (49). These cell lines do have in common with TNBC the lack of expression of ER, PR, or HER2 but that does not make them true representatives of TNBC. This difference between the TNBC cell lines and TNBC in patient samples may explain why other pathways previously reported to be involved in TNBC cell lines (GPNMP, EGFR, Notch 1–3, mTOR, AKT 1 and 2, TGFβ, activin receptor, SMAD 7) were all down-regulated in RNA-seq of the TNBC patient samples."

It doesn't address pH, lactic acid, etc. It doesn't make use of synergistic combinations which in my view is of utmost importance. Look at the inhibition of calcitriol + ketoconazole {ref}, KCZ alone almost does nothing, calcitriol alone seems to induce, whereas both together cause remarkable inhibition. 

But the result help to confirm or validate the use of certain substances!

 

 

 

Btw, here are the substances they chose:  The 7 substances of our final array are Curcumin, Burdock, Garlic, Fisetin, Korean Ginseng, Sulforaphane and Quercetin.

 

 

@chris48 I've added burdock to the diagram (STAT3 inhibition). Great find! Burdock root is actually one of 4 herbs in a tea that was used, and still is, to treat cancer, essiac tea.

 


   
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(@j)
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updated diagram


   
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and another update (attached), for links to the studies check the blog post


   
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(@j)
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Divergent effects of vitamins K1 and K2 on triple negative breast cancer cells
 
quite surprising result, 
 
"To assess differential effects of vitamin K, TNBC cells were cultured in media supplemented with K1 or K2. K1 treatment increased cell growth, and enhanced stemness and GLA-modified protein expression in TNBC lysates. Alternatively, lysates from cells exposed to vehicle, K2, or the VKOR antagonist, warfarin, did not express GLA-modified proteins. Further, K2 exposure reduced stemness and elicited anti-proliferative effects. "
 
 
 
 
 

   
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(@j)
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Kale (cooked) — 443% of the DV per serving
Mustard greens (cooked) — 346% of the DV per serving
Swiss chard (raw) — 332% of the DV per serving
Collard greens (cooked) — 322% of the DV per serving
Spinach (raw) — 121% of the DV per serving
 
Adding olive oil or eating these foods with fats, even the fats from an avocado could significantly boost K1 absorption. 
 
The low serine low lysine foods, which I consider ideal foods as part of an anticancer diet, don't contain much K1!

 


   
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(@j)
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Posted by: @j

Kale (cooked) — 443% of the DV per serving
Mustard greens (cooked) — 346% of the DV per serving
Swiss chard (raw) — 332% of the DV per serving
Collard greens (cooked) — 322% of the DV per serving
Spinach (raw) — 121% of the DV per serving
 
Adding olive oil or eating these foods with fats, even the fats from an avocado could significantly boost K1 absorption. 
 
The low serine low lysine foods, which I consider ideal foods as part of an anticancer diet, don't contain much K1!

 

The % DV is for K1, I forgot to add that. 

 


   
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(@j)
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Shikonin inhibits triple-negative breast cancer-cell metastasis by reversing the epithelial-to-mesenchymal transition via glycogen synthase kinase 3β-regulated suppression of β-catenin signaling

"shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells. Additionally, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells. Shikonin depressed cell migration and invasion, upregulated E-cadherin levels, downregulated N-cadherin, vimentin, and Snail levels, and reorganized the cytoskeletal proteins F-actin and vimentin. Shikonin reversed EMT by inhibiting activation of β-catenin signaling through attenuating β-catenin expression, nuclear accumulation, binding to T-cell factor consensus oligos, and transcription of its targeted EMT-related genes. Moreover, shikonin upregulated glycogen synthase kinase 3β (GSK-3β) levels, leading to enhanced phosphorylation and decreased levels of β-catenin. Furthermore, shikonin administration significantly inhibited lung metastasis of MDA-MB-231 cells in NOD/SCID mice accompanied by low systemic toxicity. Histological analysis confirmed that shikonin elevated levels of E-cadherin, phosphorylated β-catenin, and GSK-3β, and decreased levels of vimentin and β-catenin in pulmonary metastatic foci. These results indicated that shikonin potently inhibits TNBC metastasis by targeting the EMT via GSK-3β-regulated suppression of β-catenin signaling, which highlights the importance of shikonin as a potential candidate for novel anticancer therapeutics against TNBC."

https://pubmed.ncbi.nlm.nih.gov/31071331/

 

I've updated the diagram (attached), for links to the studies, check the blog post.


   
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(@chris48)
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@j I am repeating myself, but thank you so much for your effort! Especially these types of answers really help me to learn this stuff. I am very grateful that there are people like you spending time to explain those complex interrelationships! 🙏

 


   
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(@j)
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Posted by: @chris48

@j I am repeating myself, but thank you so much for your effort! Especially these types of answers really help me to learn this stuff. I am very grateful that there are people like you spending time to explain those complex interrelationships! 🙏

 

 

Thanks, Chris. I hope you and Bianca have a good Easter weekend!

 


   
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(@j)
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Albeit in lung cancer, I found this study on doxycycline very interesting, they also tested different doses.

" The median survival times of high-dose, middle-dose, and low-dose doxycycline groups were 235%, 197%, and 184%, respectively, compared with the control group. By contrast, the median survival time of the cyclophosphamide treatment was increased by 171%."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747360/

Mouse-to-human conversion is approx 350mg for the HD, 175mg for the MD, and 87.5mg for the LD

 

 


   
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(@j)
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I posted this in another thread yesterday and want to highlight this study, by fellow Belgians :), as it's VERY important in my view.

The metabolic waste ammonium regulates mTORC2 and mTORC1 signaling {ref}

"we reveal ammonium as a dose-dependent stimulator of proliferation"

"we show that ammonium triggers rapid and sensitive mTORC2-dependent phosphorylation of AKT-S473 in cancer cells. We show that the latter mTORC2 activation occurs via the PI3K pathway and relies on YES1 and FAK kinases, on integrin ITGβ1 and on calcium stores mobilization. In addition, our data indicate that ammonium also leads to an AKT-dependent stimulation of mTORC1 signaling and to a dose-dependent stimulation of proliferation. Our results thus identify the so-called ammonium waste as a signal impacting on mTORC2 and mTORC1 activity."

As with CRP which you want as low as possible (ref) you need to reduce ammonia as much as possible, not only through diet (reduce protein and replace with fruit mainly) but also by using substances like ornithine, citric acid, magnesium sulfate, probiotics such as lactobacillus bulgaricus and acidophilus and drugs like phenylbutyrate. For example, prior to using a promising anticancer combination such as rapamycin with doxycycline, I believe it would be good to focus on reducing ammonia as much as possible.

 

 

 

 


   
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(@rosed)
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@j Thank you so so much for this post, Johan!!!!!!!   So grateful to you for all of this information. God bless you for this.   Need to check my probiotics! You probably mentioned this before.... but is there any natural equivalent to phenylbutyrate?   Happy Easter to you.


   
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Posted by: @rosed

@j Thank you so so much for this post, Johan!!!!!!!   So grateful to you for all of this information. God bless you for this.   Need to check my probiotics! You probably mentioned this before.... but is there any natural equivalent to phenylbutyrate?   Happy Easter to you.

@rosaleend Unfortunately, there isn't. PB is very expensive but there's a generic option available since the patent has expired ( https://www.canchema.com/product/sodium-phenylbutyrate-4-pba/).

Butyrate (sodium butyrate, tributyrin) also helps to lower ammonia although less effectively, and as PhenylB, butyrate is an HDAC inhibitor.

The Effect of Different Probiotic Bacterial Strains on Ammonia (NH3) Production Levels
(Lactobacillus bulgaricus, Lactobacillus acidophilus, Bifidobacterium longum, Saccharomyces boulardii)
 
I've attached the updated diagram.
 
Thanks, and happy easter to you too!
 

 

 

 

 


   
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(@j)
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The Effect of Different Probiotic Bacterial Strains on Ammonia (NH3) Production Levels
(Lactobacillus bulgaricus, Lactobacillus acidophilus, Bifidobacterium longum, Saccharomyces boulardii)
 
AND Lactobacilli Modulate Hypoxia-Inducible Factor (HIF)-1 Regulatory Pathway in Triple Negative Breast Cancer Cell Line
 
Lactobacillus rhamnosus stood out and can inhibit hif1alpha

 


   
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(@j)
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some options to inhibit several processes


   
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(@rosed)
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@j Thank you so much!


   
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(@j)
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Posted by: @j

some options to inhibit several processes

updated, added studies 

 


   
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@rosaleend @chris48 @jens

Integrated omics-based pathway analyses uncover CYP epoxygenase-associated networks as theranostic targets for metastatic triple negative breast cancer

https://jeccr.biomedcentral.com/articles/10.1186/s13046-019-1187-y#citeas

We observed a 2- to 10-fold increase in the gene expression of CYP2C19 and CYP2J2 in the triple negative mammary tumor tissues compared with the paired normal tissues.
A strong association between decreased survival and overexpression of CYP2J2
Overexpression of CYP2C19 in TNBC patients showed a less pronounced correlation to survival rate

Tamoxifen is an inhibitor of CYP2J2!

 

 


   
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"We have identified six TNBC-related signaling nodes, including Myc, Ras, MAPK, EGFR, HIF-1α and NOD1/2, which may be used as a gene signature for CYP epoxygenase overexpressing triple negative mammary tumors. Inhibitors or antagonists of their corresponding proteins may be considered as an approach for intervention of CYP epoxygenase overexpressing TNBC."

Caution: Omeprazole and lansoprazole enantiomers induce CYP3A4 in human hepatocytes and cell lines via glucocorticoid receptor and pregnane X receptor axis

 


   
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ketoconazole, a CYP3A4 inhibitor, used in combination with calcitriol showed remarkable inhibition in vitro 

https://www.pnas.org/doi/10.1073/pnas.2104162118


   
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IVM could be added to an integrative treatment strategy to inhibit IL-6 (see diagram).


   
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