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Jcancom
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31/07/2020 3:20 am  

There are just so many complex and convoluted aspects of cancer metabolism that provide potentially new avenues of vulnerability. This article helps to redefine the purpose of respiration. Isn't the purpose of respiration obvious in cancer? Recycle NADH, make ATP, maintain an electrochemical gradient in the matrix etc.? This is fairly basic and presumably firmly established science. Yet, perhaps there is an until now hidden reason behind OXPHOS ... support asparate biosynthesis? If so, then selectively inhibiting OXPHOS along with supression of the asparate pathway might be of help.

https://pubmed.ncbi.nlm.nih.gov/26232225/

 

 

 

 


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Jcancom
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01/08/2020 1:42 am  

This is another great metabolic masterpiece. Shut off MCT1, shut off the glucose supply to hypoxic cancer cells. It all begins to make intuitive sense. One could treat cancer as a Gedankenexperiment and only use the scientific literature to confirm what you have deduced.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2582933/

 


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Jcancom
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01/08/2020 7:27 pm  

This is extremely interesting! The attached file includes all human genes with their typical expression patterns in different tissues. Scientists have already used resources similar to this to discover that FerT is almost exclusively active only in cancer cells. The file below includes FerT (search for it in the second sheet of the spreadsheet.). However, this file suggests that FerT might be somewhat more widely expressed than exclusively in the testes. Wonder how accurate and complete this research is?

(I attached the full spreadsheet, probably could have simply included the url and saved space on the hard drive.)

This approach of looking for genes that are non-active in typical normal cells could have more widespread importance than I would have previously thought. As can be seen in the spreadsheet ( use the sort command for the different tissue columns), there are actually quite a fair number of genes that are (from current knowledge) not widely expressed elsewhere; for some reason the reproductive system appears to have many of these dedicated genes. What the e260 research with FerT found was that cancer sometimes can find a way to reactivate these genes for its advantage. If this did actually occur with some frequency in these largely inactive genes, then this might be a useful approach to consider more broadly in cancer management.  

https://www.broadinstitute.org/files/shared/metabolism/mitocarta/human.mitocarta2.0.html

 

 


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Jcancom
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01/08/2020 8:56 pm  

The amino acids glycine/serine have attracted interest as their depletion has shown anti-cancer effects. In the figure below I am particularly attentive of GSH as it goes to the TCA and ROS. I think we can all remember how powerfully the 3-BP patient with melanoma responded when GSH was knocked down. LDH almost went to zero on the second treatment. GSH is a potent protector of the cell against ROS and "xeno-biotics" such as 3-BP. It seems to conjugate to any strange molecule that it encounters. However, once the cancer cell's GSH supply is exhausted, it is defenseless.

https://www.sciencedirect.com/science/article/pii/S0968000414000280

https://www.nature.com/articles/nature22056

 

Metabolic medicine have consistently been depicted on forum as nice, virtuous and modern approaches to managing cancer. The articles that I read about glycine/serine and then how this feeds into so called 1 carbon metabolism/folate cycle etc. noted that such presumed virtuousness might be somewhat illusory. Anti-folates were at the leading wave of cancer chemotherapy in the 1940s. Clearly disturbing some metabolic pathways can lead to side-effects and this is possibly why the pharma have avoided targeting even more centrally located pathways such as glycolysis.

 

http://cology4u.blogspot.com/2011/06/anti-cancer-drugs-i.html


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Jcancom
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11/08/2020 2:57 am  

This is from D's article on the oxaloacetate thread. I greatly enjoy these visual summaries as they are able to succinctly provide the main features of a treatment rationale. We are now accumulating quite a few of these figures on this thread.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911603/

 

 


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Jcancom
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12/08/2020 12:19 am  

Yet, another good one. This is a little complicated and the figure below does not entirely show the mechanism so here goes. DERL3 when hypermethylated can lead to overexpression of SLC2A1 [Glut1] (glucose intake). When you down express DERL3 it can reduce glucose intake and tumor growth. A1 The somewhat tricky part here is that PKM2 has regulatory control over DERL3 expression; shikonin is a PKM2 inhibitor and it can downregulate DERL3. Upwards of ~50% of breast tumors express DERL3 (other largish expressions are in heaptoceelular, esophagus,prostate, head and neck, colorectal etc.). There was a noticeable survival benefit in patient series that had unmethylated Derl3 gene expression [hypermethylation DERL3 --> high SLC2A1 = BAD].   

https://pubmed.ncbi.nlm.nih.gov/24699711/

 

 

 

 

 

 

 


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Jcancom
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12/08/2020 2:39 am  

I remembered one of my old posts today from the forum and was able to locate it in my activity folder. I could not quite remember the name glycine/glycerol? I found it: the treatment was butanol/glycerol.


This is sort of a strange one. Apparently back in the 1950s these researchers came up with what would seem to be a fairly unique theory of cancer based upon urinanalysis. What they found was that Type "A" imbalance was reflected by low specific gravity of urine and high pH, low chloride index and high surface tension. The opposite (i.e., high specific gravity, low pH, high chloride index and low surface tension) was called Type "D" imbalance. The treatment oddly reported several impressive responses (We are not told the n of the denominator).

...  "Those inducing acidification were thus classified as an "inducing offbalance type A," or "anti offbalance type D" or "anti D," while those producing alkalization were called "inducing D," or "anti offbalance type A," or "anti A." Using this method, we could determine that elements such as Li, K, Na, Fe, Ni, Zn, Hg, Bi, B, F, CI, Br, I—in sufficient amount—produced in the s.d.c. pH an acidifying effect. The opposite effect—alkalization—was seen for Mg, Ca, Sr, Ba, Cu, Pb, S and Se. It must be emphasized that some elements—such as K, Fe, Zn, Hg, CI in the acidifying group and Ca, Cu, S and Se in the other—produced an intense effect while others had a weak though still clear, action. Off balance Type D is treated with butanol/glycerol."  From the above we can recognize that they have a strong acid/alkaline perspective.

Find the section heading "Butanol, Glycerol Cancer Treatment" for some patient reports.

The reports are much more impressive than I would have expected given the theory they developed. It is especially impressive that they appear to have an actual biomarker that can guide treatment.

The treatment itself: glycerol--  glycerol is largely considered safe in the doses that they are discussing.

Butanol is somewhat less clear. Butanol is chemically similar to ethanol but is described as more toxic. Might want to do more reading on this (see url below).

Given that these treatments are adjacent to the major metabolic pathways it is not misplaced to also call  them metabolic in nature.    

https://chestofbooks.com/health/disease/cancer/Emanuel-Revici-Research-Physiopathology/Butanol-Glycerol-Cancer-Treatment.html

 

https://www.google.nl/url?sa=t&rct=j&q=&esrc=s&source=web&cd=2&ved=0ahUKEwjvm6bYydPSAhVLCcAKHfwDBWQQFgghMAE&url=https%3A%2F%2Fofmpub.epa.gov%2Feims%2Feimscomm.getfile%3Fp_download_id%3D504783&usg=AFQjCNHaPV-L2wUhsVJC0NhDrkLq4xr__Q&sig2=m33xF9ZEoShN4NNCGgodBA

 

 

 

Glycerol

 

 


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Jcancom
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12/08/2020 3:25 am  

I suggest that those on the forum take a look into the url below. The findings are quite interesting. For example, it was found that various pain in the body could be controlled by simply adding acid or adding alkaline (go to the url and look for the  Chapter 4 note 2 ... as below). I suspect that a great many people are coping with pain and do not realize that a remedy might be available.

I believe that in the past that D was not entirely favorable on the acid/alkaline approach to cancer. Yet, Figure 208 from the url has me wondering. Urine pH could be increased by 2 pH units within 1 hour using sodium bicarbonate. That is a 100 fold change! I remember some of forum who tried to changed their pH eating vegetables; it wasn't overly easy to do that. However, there has been some question about the safety of sodium bicarbonate treatment. Many interesting observations from the url below, the ideas presented seem to be a time in which medicine was much more exploratory. It is not entirely clear to me that the performance of modern day medicine greatly exceeds that presented on the website below.

  https://chestofbooks.com/health/disease/cancer/Emanuel-Revici-Research-Physiopathology/Chapter-4-Note-2-Blood-Titrimetric-Alkalinity-And-Urinary-Ph.html

Chapter 4, Note 2. Blood Titrimetric Alkalinity And Urinary Ph


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Kimster
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12/08/2020 11:02 am  
Posted by: @jcancom

 I remember some of forum who tried to changed their pH eating vegetables; it wasn't overly easy to do that.

Hi friends, just would like to share the following that noticed recently - but sorry as not relevant to the main topic:

 

https://www.canceractive.com/article/How-to-alkalise-your-acid-body

How to alkalise your acid body

9 August 2020

 

Other information from this website:

https://www.canceractive.com/article/why-you-need-an-acid-gut-and-an-alkaline-body

Why you need an acid gut and an alkaline body

9 July 2017

 

Thanks.

Kimster


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Daniel
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12/08/2020 5:08 pm  

@kimster Thanks a lot! I will check and let you know my view!

 

Kind regards,
Daniel


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Kimster
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12/08/2020 5:36 pm  
Posted by: @daniel

@kimster Thanks a lot! I will check and let you know my view!

 

Kind regards,
Daniel

Hi Daniel, thank you very much for taking note of that website's information --- really looking forward to reading your views later 🙂

 

Thanks.

Kimster


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Yudaitheska
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14/08/2020 2:18 am  

@jcancom

Speaking about metabolism and autophagy... 

https://www.nature.com/articles/s41467-020-17882-2

Here, we show that autophagy (i.e., lipophagy) maintains energy metabolism by suppling free fatty acids (FFAs) to mitochondria through the degradation of LD in AML cells, but not in normal hematopoietic cells. Furthermore, we demonstrate that mitochondria modulate lipid catabolism through the regulation of the autophagy process. Our study also reveals that the control of autophagy by the mitochondria, and then the regulation of lipid availability require the maintenance of the tethering between the ER and the mitochondria membranes referred as the mitochondria–ER contacts or MERCs24. Thus, this study reports a new regulatory loop, in which mitochondria control their own energy and respiratory sources through the regulation of autophagosome formation at MERCs, necessary to AML cell proliferation and survival in vitro and in vivo


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Jcancom
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15/08/2020 7:13 pm  

Yud, thank you for another again powerful insight into metabolism. Metabolism truly is such a pervasive aspect of cancer biology. The biochemical features that we are constantly discussing are endlessly recycled and redeployed in nearly endless combinations and patterns. I think it is helpful to always be thinking: How does this relate to metabolism? As we have seen repeatedly, central aspects of metabolism are almost always involved. Studying biochemistry through the lens of cancer would help to give real world meaning to virtually all major pathways.

It is still quite startlingly to see how the article you noted integrates autophagy, OXPHOS and lipids. We have somewhat casually accepted OXPHOS inhibition as a strategy for cancer management. It is of interest to see how this can affect other parts of the metabolic network.

I have wondered about beta-oxidation and how it might be part of an anti-cancer strategy. Beta-oxidation produces so much NADH (directly and then through Krebs), FADH2 (directly and through Krebs) and also some ATP (through Krebs). One might wonder how turning on Beta-oxidation along with suppressing OXHPOS might stress cancer cells. A great deal of NADH and FADH2 would need to be processed and there would not seem to be an easy route to process it (given OXPHOS inhibition).    

 


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Jcancom
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15/08/2020 7:18 pm  

Yud, I am interested in your opinion of the treatment that I noted above butanol/glycerol . This seemed to be a fairly powerful treatment in patients during the 1940s, 1950s ... . I am not entirely sure about how this would fit into metabolic theory though they both have clear metabolic like character. Perhaps this might be worthy to try in the veterinary setting to which I believe you have referred to previously. 


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Jcancom
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15/08/2020 7:19 pm  

 

Your comment twigged a recollection of one of the newly published 3-BP formulations. Typically, autophagy is an escape mechanism for cancer, in this new research they were able to convert autophagy into a pro-apoptotic signal. 

... "More importantly, the autophagy level was significantly elevated by the combination of 3BP and PDT determined by Western blot, immunofluorescent imaging, and transmission electron microscopy. It was very surprising that excessively activated autophagy promoted cell apoptosis, leading to the changeover of autophagy from pro-survival to pro-death."

Another great illustration of metabolic medicine, Yeah!                                                                         In the below diagram they are not merely targeting one of metabolic pathway; they have managed to stress most of the major pathways that we constantly speak of: pH, glycolysis/OXPHOS, hypoxia, ROS, autophagy. Hmm, what happens when they combine this and achieve synergy?                                       https://pubs.acs.org/doi/10.1021/acsnano.0c01350

 

 


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Yudaitheska
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19/08/2020 2:32 am  

@jcancom

Hello J! It took me a while to answer since I wasn't familiar with the use of glycerol and butanol for cancer treatment. I read the articule saw the pictures and was intrigued... So I started researching... For what I have been able to read seems like butanol might be an LDH inhibitor..

In bacteria pyruvate can be transformed into acetyl co A, lactate or butanol.. 

https://m.x-mol.com/paper/1212943404365586438?adv

In this article the seem to suggest that, then I started reading other articles about how they obtain butanol from fermentation.

It'd be interesting to try in animals, whatever you can mix into food without a weird smell will be ingested. 

I will look in to it.

Thank you! 


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Jcancom
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19/08/2020 3:38 am  

Yud, this is great!

I have been wondering about this glycerol/butanol treatment idea for a while, though it seemed quite strange to me and I wasn't sure how to bring it to the attention of others. The theory that they presented in the url that I linked about urinanalysis seemed somewhat odd. Yet, glycerol clearly is a fairly centrally located metabolic chemical, it is, in fact, nearly a direct precursor to glycolysis. Perhaps glycerol gets "stuck" because the enzymes required to make the conversion are defective sometimes in cancer. The acid/base idea that you noted also was referenced in the link. If this is changing tumoral pH balance then lactate dehydrogenase could certainly be involved with that.

One other aspect I found of interest is that the reference talked about butanol being toxic. Yet in the dosing range given to the humans from the link this did not appear to manifest. Butanol is described as much more toxic than ethanol.

I have to admit it is very comforting that I can make a suggestion such as glycerol/butanol and others on forum will pick up on it. When one has to always carry one's pack it can become tiring.

Glycerol/butanol does look like a good one even though it has become obscured with the passage of time. It certainly should make us sit up and take notice when we read the url which describes patients with very serious metastatic illness several of whom had long term responses to what appears to be glycerol/butanol duotherapy. It is a fantastic feature of the internet that the wisdom of the past has been so well preserved and is now easily available to all.

{It was quite funny when D found the article from the British Medical Journal from the ~1800s which described doctors successfully treating cancers with acids (?), I believe that this was in reference to citric acid. I suspect a fair amount of the medical headlines that we read on a daily basis might be mere repeats from one hundred or more years ago.}    

Glycerol is described as non-toxic (and odorless) and appears to be a widely available chemical. One would need to be careful though as there was a serious incident a few years ago when a mislabeling incident lead to widespread fatalities. Butanol is described as having a highly alcoholic aroma.

I will be very interested to hear what results you might share with us. Please keep us posted!

J

 


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Jcancom
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20/08/2020 3:37 am  

This one is just over the top. It includes about 10 metabolic treatments, one of which is mito-3-BP which by itself is very very startling. It is disappointing thought that they did not advance the science of 3-BP in this new article it has been years and years and we have heard nothing more about mito-3BP. I am very interested to see what might happen with it in vivo. Directly dragging 3-BP into the mitochondria could be extraordinarily powerful, though I am somewhat unclear about its safety.

 

Here's another one from the article Mg2Si nanoparticles: it acts as a deoxygenating agent and is activated by an acidic environment; the only product that remains is SiO2. Taking away the oxygen from cancer cells would force them to be obligate glycolytic cells. Forcing cancer down specific metabolic pathways can wind up trapping them into energy crises etc. where no escape routes exist.

 

 

 

 

 

There are several more highly impressive results. The approach below uses GOD (Glucose oxidase). Other research has used a similar approach; the products are oxygen and gluconic acid which can also be a powerful anti-cancer strategy. 

 

 

 

 

This one blocks out lactate production which could also be highly effective.

 

 

 

Finally 2-DG and Black phosphorus nanosheets (The article notes that BP nanosheets "have been extensively used in various biomedical applications") were found to have synergistic effects in vivo. The BP nanosheets block autophagy -- amplifying the effects of 2-DG.

 

 

 

There are a great number of quite powerful metabolic approaches described in this article. I would have liked to see what they might have been able to do with minicells, oncolytic viruses and X-Ray PDT. The metabolic technology that is assembling will have extremely large anti-cancer treatment effects.

https://onlinelibrary.wiley.com/doi/10.1002/advs.202001388

 


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Jcancom
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20/08/2020 5:02 pm  

This is very very exciting! I think I have thought of a truly powerful combination treatment. I will post this combination step by step.

 

Step #1: Treat with anaerobic bacteria Clostridium novyi-NT.

As the figures below illustrate these bacteria will become resident in the hypoxic cores of the tumor. This approach is expected to be inherently safe because the bacteria cannot survive in environments with oxygen, they have been genetically engineered to be safer, and antibiotics are effective in controlling them. Clinical trials are ongoing with CN-NT.

http://www.cancerjournal.net/article.asp?issn=0973-1482;year=2018;volume=14;issue=8;spage=1;epage=6;aulast=Wang

 

 


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Jcancom
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20/08/2020 5:39 pm  

Step 2: Treat with a DOA (a deoxygenating agent). This is a figure that I posted above though I will add some more description.

Here is the chemistry involved.

MG2Si + 4 H+ --> 2MG2+ + SiH4      (1)

That is, magnesium silicide + hydrogen --> magnesium + silane    (1*)

The article reports silane as being non-toxic.

SiH4 + 2O2 --> 2H2O + SiO2  (2)

That is silane + oxygen --> water + silicon dioxide  (2*)

Total Equation with the silane intermediate excluded

MG2Si + 4 H+  +  2O2 --> 2MG2+ 2H2O + SiO2   (3)

 

What we can see happening is that magnesium silicide will withdraw oxygen from the tumor environment selectively. This is because the H+ on the left side of the equation is acidic and will be much more present in the cancer environment (pH is a logarithmic scale, so there is a 10 fold difference between 6.5 and 7.5 pH in H+ concentration).

The article notes that silicon dioxide could aggregate in the cancer environment I am not entirely sure if this would be safe (perhaps ischemia could result?). Also it would be good to know more about the safety of silicon dioxide itself, though it appears mostly benign.

The Figure labeled c below shows how silane is attacked by O2 with silicon dioxide and water remaining.http://www.w3.org/1998/Math/MathML" altimg="urn:x-wiley:21983844:media:advs1836:advs1836-math-0001" display="block" location="graphic/advs1836-math-0001.png"><mtable displaystyle="true"><mtr><mtd columnalign="right"><mrow><mi mathvariant="normal">M</mi><msub><mi mathvariant="normal">g</mi><mn>2</mn></msub><mi mathvariant="normal">Si</mi><mo>+</mo><mn>4</mn><msup><mi mathvariant="normal">H</mi><mo>+</mo></msup><mo>→</mo><mn>2</mn><mi mathvariant="normal">M</mi><msup><mi mathvariant="normal">g</mi><mrow><mn>2</mn><mo>+</mo></mrow></msup><mo>+</mo><mi mathvariant="normal">Si</mi><msub><mi mathvariant="normal">H</mi><mn>4</mn></msub></mrow></mtd></mtr></mtable></math>">g2Si+4H+2Mg2++SiH4

Figure labeled e shows the extremely powerful result of the treatment. The large yellow and red glowing blobs illustrate how powerfully oxygen is depleted and glucose (?) is by consequence upregulated (not sure if they are using PET 2-DG imaging). The figures shows that this widespread tumor hypoxia lasts for HOURS! I would want to see systemic dosing in vivo, as I am unclear whether the hypoxia might extend beyond the tumor mass and into the surrounding circulation. If the treatment grabbed all the oxygen from the blood supply that could be a problem,

Nevertheless, if these concerns could be addressed (as they likely have been) this would be an extremely powerful treatment. Taking the oxygen supply from cancer would have a dramatic effect on the tumor mass. Foremost would be conversion of the cancer cells into obligate glycolytic cells. OXPHOS would no longer be possible as oxygen is definitely required for OXPHOS.

What is especially powerful is that the treatment in Step 1 would greatly enhance the treatment effect. In Step 1 we see that the bacteria are confined to the hypoxic core of the tumor because they must live in an oxygen free environment. What is so powerful here is that the treatment in Step 2 extends out this hypoxic region to the entire tumor mass! The bacteria that have been seeded into the tumor cores can now reproduce logarithmically possibly for a few hours! With an order of magnitude growth per hour after a 5 or more hours the entire tumor mass could become almost completely saturated with these bacteria. The metabolism of the tumors might essentially collapse. 

To add more metabolic stress we can move on to Step 3.  

  http://www.w3.org/1998/Math/MathML" altimg="urn:x-wiley:21983844:media:advs1836:advs1836-math-0001" display="block" location="graphic/advs1836-math-0001.png"><mtable displaystyle="true"><mtr><mtd columnalign="right"><mrow><mi mathvariant="normal">M</mi><msub><mi mathvariant="normal">g</mi><mn>2</mn></msub><mi mathvariant="normal">Si</mi><mo>+</mo><mn>4</mn><msup><mi mathvariant="normal">H</mi><mo>+</mo></msup><mo>→</mo><mn>2</mn><mi mathvariant="normal">M</mi><msup><mi mathvariant="normal">g</mi><mrow><mn>2</mn><mo>+</mo></mrow></msup><mo>+</mo><mi mathvariant="normal">Si</mi><msub><mi mathvariant="normal">H</mi><mn>4</mn></msub></mrow></mtd></mtr></mtable></math>">i+4H+2Mg2++SiH4

https://onlinelibrary.wiley.com/doi/10.1002/advs.202001388


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Jcancom
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20/08/2020 5:41 pm  

Step 3:

Adding in anti-glycolytics could now be very effective. The cancer cells are obligate glucose consumers. Stressing glucose metabolism could then push the cancer cells into an energy crisis. Fenbendazole, metronomic 2-DG ... could be quite effective.

 


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Jcancom
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20/08/2020 6:02 pm  

Addons:

There are several add-ons that could enhance this combination. One that could be helpful is viral therapy. Perhaps the anaerobic bacteria could be infected with (or a carrier for) an oncolytic virus (OV). These bacteria would then be like little robotic machines delivering the OV directly to the core of the tumor where the immune system is perhaps excluded. The OV could then grow exponentially (as they are also anaerobic) largely beyond the suppressive ability of the immune system. This trick would work on every round without resistance (assuming that the bacteria do not provoke an immune response) because the bacteria are depositing them outside of the immune system. These OVs would then also place a large metabolic burden on the cancer cells which only have glucose as a fuel.

Also of note is that now that the entire tumor mass requires glucose and is producing lactate, the level of lactate could greatly increase (This could clearly be dangerous as the acid level in the body could also greatly increase, though it might be useful therapeutically if it this could be managed). With the lactate shuttle, some cancer cells are producing lactate (the "far" cancer cells), and some cancer cells are consuming the lactate (the "near" cancer cells). In such a scenario the actual amount of lactate produced could be greatly obscured. Yet, when you turn off this lactate shuttle [because the "near" cancer cells are now also obligate glucose consumers] (this could be made true if necessary by treating with MCT-1 inhibitors), none of the cancer cells would then be consuming lactate. The deoxygenating agent will ensure that even with oxygen "available", that this oxygen will be consumed in the chemical reaction producing silicon dioxide and water. If 11 lactate are produced and 10 lactate consumed with a net of 1 lactate that is then sent to the blood supply, then shutting down oxygen might result in 21 lactate produced and none consumed. That is the lactate concentration might dramatically increase (perhaps by 21 fold?). The toxin of the cancer cells could then be toxic to them. With that much lactate in their environment the cancer cells could become greatly stressed, and they might also then become yet more vulnerable to acid targeting therapy as they would then be even more highly acidic and thus targetable.

     


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Jcancom
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20/08/2020 6:08 pm  

The combination idea above could be an extremely powerful treatment approach. Various other treatments that we are familiar might also be considered. For example, proton pump inhibitors, ketogenic diet, possibly the idea from the above post of creating a biological machine for the general circulation that would convert lactate to pyruvate, pro-oxdiants stress stress such as paracetamol which would then drain precious ATP, and many others.

I am interested in comments from those on forum to my suggestion. The one component that is somewhat at the experimental stage is the DOA, though it is possible that there are other similar deoxygenating treatments that could be substituted for it. 


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Jcancom
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20/08/2020 9:36 pm  

I think the series of posts that I have given above are close to the most powerful treatment that I have imagined to date for cancer. Notably, resistance would essentially not be possible. Cancer does develop resistance though this resistance is in relation to genetic mechanisms: some cell will find a way around a targetted treatment etc. or MCT1 expression is lost. This cell can then create a new colony that is resistant. In this sense close to 100% of cancers develop this type of resistance and is why long-term survival from metastatic cancer has for most of human history approached 0%.

Yet, another type of resistance: biological resistance which could be suggested for the above idea is much less obvious. In order to escape the above treatment the anaerobic bacteria would need to be intercepted (however, they could be formulated to hone to acidic environments). Once at their desired locations it is not obvious to see how the cancer could resist the treatment. The Second step of removing oxygen also seems to be a given of biology as does the obligation of the cancer cells to now become obligate glucose consumers. It is probably too optimistic that the above idea would encounter no problems, though very few problems would seem to be in the way.

 


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Jcancom
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22/08/2020 10:44 pm  

I want to intensify all of my metabolic posts into this one thread. Here is my previous post about the circadian clock and glucose/OXPHOS. The surprising finding was that glucose/lactate levels were highly cyclical. Of course, this should not be that surprising at all, a spike in glucose after breakfast and dinner is what one should expect. 

Melatonin is behaving like DCA by blocking PDK. Would be interesting to know whether perhaps these two would synergize. It also gives one the idea that perhaps certain treatments especially e.g., 3-BP and others should coordinate with the circadian rhythm. This might not seem overly powerful until we remember the result with the blue tinted cage. Mice were kept in blue tinted cages or non-tinted cages. This one difference perhaps through melatonin had a large effect on the size of their tumors. If anyone could find this result on the forum please post the url here. 

Here's the thread url: https://www.cancertreatmentsresearch.com/community/natural-substances/chronotherapy-with-melatonin-night-time-anti-glycolytic/#post-3333

 

http://www.melatonin-research.net/index.php/MR/article/download/44/364?inline=1

 

 

 


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Jcancom
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23/08/2020 2:46 am  

I want to repost this one here so that all of the metabolic posts can be in one convenient place.

More metabolism-- thiamine and cancer. Another PDK inhibitor along with DCA and melatonin? Thiamine has quite a few metabolic functions. Article also speaks of how Asians and Africans have high thiaminase, a natural thiamine-degrading enzyme, in their diets. The point is stressed that vitamins should not be automatically be assumed to be benign. In some circumstances even a B vitamin might have cancer promoting effects. 

https://cancerandmetabolism.biomedcentral.com/articles/10.1186/2049-3002-1-16#Fig4

 


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Jcancom
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23/08/2020 2:47 am  

And another repost. The journal Cancer and Metabolism could offer us a great many new insights into the metabolism of cancer.

Yeah! The article I posted previously about the metabolism of thiamine was from the journal ah Cancer and Metabolism. It sort of gives away right there an entire journal that discusses Cancer and Metabolism. Sounds great! This is gold!

 

These articles open up an entirely new metabolic landscape. We have mostly stuck with the central biochemical pathways of glycolysis etc.. Some of these articles start reaching deeper into the metabolic network. This one looked at NAD+ chemistry from an off-glycolysis perspective. Here they used FK866 to inhibit NAMPT. Bottom line when they did this the central result for 2 different cancer cells was addiction to LDHA production of NAD+. This research would allow us to step deeper into pathways and possibly magnify some of the treatments that we have examined. For example, I would be interested to see how this might combine with syromet.

Driving cancer cells down predefined metabolic alleys (secondary biochemical branches) could be of significant value. Here again we see that ultimately when cancer is driven down an alley it will wind up back on one of the main highways that we are always discussing without limits. The confusion and uncertainty of cancer begins to resolve: almost no matter what metabolic path you stress, you are going to wind up back somewhere very familiar. Resistance does not need to imply that tumors can achieve escape. As we see here the cancer cells were unable to escape treatment their only escape route was to break into jail! Basic strategy might then be to treat with one of these secondary pathways to drive it into the open and then once tumor addiction has occurred to treat with a closer such as syromet.

So the idea is drive addiction on a secondary pathway to flush out to one of a handful of main processes (i.e., e.g. glycolysis), then treat with a generic therapy for the win.     

 

https://cancerandmetabolism.biomedcentral.com/articles/10.1186/s40170-018-0174-7

 

 

 

 


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Jcancom
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23/08/2020 3:56 am  

Very exciting! So much excitement!

Remember a few years ago they found that Brazilian bee venom targeted proteins on cancer cells but not normal cells. Nothing ever seemed to happen with that treatment. Apparently something did happen.

This treatment used that basic idea. And even more interestingly a phase I clinical trial has already been completed and it was found to be safe. Of even more interest from the metabolic perspective is that one feature of cancer cell biology that upregulates the tumor destruction effect is oxidative stress. Oxidative stress is one of the central metabolic features that we talk about relentlessly. A metabolic treatment of increasing oxidative stress along with a cancer cell membrane disruptor might have anti-cancer effects.

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950924/pdf/12964_2019_Article_476.pdf

 

Fig. 1

 


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Jcancom
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Posts: 510
23/08/2020 6:31 am  

Another metabolic approach to cancer management. GLO1 is known to be upregulated in many cancers. GLO1 detoxifies methylglyoxal with the result of more lactate production and then OXPHOS is upregulated. What if we knock down GLO-1 and cotreat with MG? The cancer is trapped again by its own contortions. Research has found this to be a strong combination in vivo.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589625/pdf/oncotarget-08-54838.pdf

 

Apparently, triple negative breast tumors use this upregulation of GLO1 escape mechanism for methylglyoxal stress. The below metabolic diagram offers one possible work around. One could treat with e.g., nanomethylglyoxal, and then inhibit GLO1.

Curcumin is known to be a strong GLO-1 inhibitor, perhaps as nano-curcumin. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2567432/pdf/pone.0003508.pdf

To finish the combination, one could then treat with shikonin as suggested below. Also an OXPHOS 1 specific inhibitor could be helpful for the below strategy. Interestingly, methylglyoxal is a specific OXPHOS 1 inhibitor.

 

https://www.sciencedirect.com/science/article/abs/pii/S0003986117306963

Many good effects of inhibiting GLO1. For example, reducing Lactate levels. Lactate causes a great number of problems.

 


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Jcancom
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Posts: 510
23/08/2020 11:15 pm  

I am reposting this from a fen thread so that all the metabolic posts can be concentrated together. This post is highly relevant. Cancer has a substantial effect on pH inside and outside of cancer cells. The H+ that is pumped out with lactate creates a highly acidic cancer environment which creates large amounts of problems for the immune system surrounding cells etc.

What is also of interest is that I have read that glycolysis itself should not be thought of as creating acid but actually deacidifying. Glycolysis is using up H+, this is probably why the intracellular pH of cancer is actually alkaline. I think there was some mention that using glycogen reduces the net amount of H+   https://journals.physiology.org/doi/full/10.1152/ajpregu.00114.2004?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org

 

One of the current ideas that I am contemplating relates to acids/bases. In a previous post I noted how many of the treatments that we are interested in are "ates". Citrate, 3-Bromopyruvate, oxaloacetate, there are a great many others. These are the conjugate bases for citric acid, 3-Bronmopyruvic acid, etc.. This is highly speculative at this point though here is what I have so far.

What I am wondering is whether "an acid shuttle" effect might be occurring. When lactate is expelled from the cell an H+ is symported out as well. This will acidify the tumor environment. However, this is only true due to the pKa of lactic acid being ~3.9 (at pH 7.4).

Look at the figure below for acetic acid. It has a pKa =5. At a pH of 5 half of a volume of acetic acid will be in the acid form on the left side of the left figure below; half will be in the conjugate form on the right side of the left figure below. Yet as shown below when the pH moves down to pH=1 almost all will be in the acid form on left and all will be in the conjugate base form on the right at pH=8. With the formation of a salt perhaps sodium acetate to follow?

What this seems to imply is that the cancer environment is just not acidic enough. If the cancer environment could be brought to a pH of 3 (i.e., below the pKa of lactic acid) then the conjugate base (lactate) would gain an H and become lactic acid. In a very acidic environment lactic acid would deacidify the environment by grabbing the Hs. This observation is not overly helpful as the Hs in the cancer environment from the symport with lactate are causing the acidic environment. If lactic acid did start grabbing the Hs then the cancer environment would become more basic and as this happened the lactic acid would start dumping the Hs back which would cause another round of acidification.  Basically it seems that it is stuck with a damaging acid/base balance.   

pH pKa example.png

{I am very unclear whether this line of reasoning is in fact correct. If charges were to emerge than other substances such as Na+ might simply form salts. This itself might be of interest in cancer management.}

What I was considering though was whether a shuttle effect might not apply. Let's say that you have acetic acid floating around the blood stream at physiological pH of ~7.4. It would then be in the conjugate base form on right side of left figure above. It will have a charged o- as seen. What is of interest here is that cancer cells have a negative surface charge.  

https://link.springer.com/article/10.1007/s41048-018-0080-0   

So acetate (the conjugate base of acetic acid) will be magnetically repelled from cancer cell surfaces (Cancer cells have a negative surface charge due to the lactate grabbing H+ from the cell surface when leaving when the cancer pH is >~5.5. Sorry everyone there is another exciting figure to include here to show what I am trying to say in words. I am sure that D has spoken of this many times before because this is very important with respect to how cancer drugs can access cancer cells. 

Clearly thinking about cancer in this electronic way as the article reports can be very powerful. With a negative surface charge on the cancer cells, positively charged particles would be magnetically attracted to cancer in a way that they would not be to normal cells. The technology they describe uses this very concept to target probes to cancer cells. Targeting therapeutics with the same approach would seem to be a highly promising idea. 

Nonetheless, what I am trying to think through is how an acid shuttle might work. What you could have is a molecule  such as acetate. In non-cancerous body regions the pH = ~7.4 --> no H attached. When the acetate molecule reached the cancer environment (assume pH=4), the acetate then grabs an H+ and is now acetic acid. When this acetic acid molecule leaves the cancer environment as it travels through the bloodstream it would then drop off the hydrogen and become acetate again. There is an acid transport effect occurring. I wonder whether this could be used as a therapy? Perhaps shut off lactate production, treat with an acid shuttle chemical causing a rapid increase in cancer pH. I think an article spoke of such a strategy of manipulating the extracellular pH ( not sure whether they suggested lowering or raising pHe). The above reasoning is trying to find the underlying biological reason that so many of the "ate" are found to be cancer fighters.

If anyone could find the pKa of 3-BP, please post! 

 

figure1


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