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Jcancom
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This is from the wiki article on omega-3 fatty acids. The second column has x:y where x is the number of carbons and 6 is the number of double bonds. Simple DHA has the most at 6; so does nisinic acid.

D, the metabolic story just goes on and on. It is startling. Often we wind up right back with drugs that we are all too familiar with. The 3-BP --> diclofenac plan above is especially intriguing. The escape routes for cancer are narrower and narrower. On the DCA thread we talked about how to strategically plan the second treatment for maximal effect. With this 3-BP- diclofenac treatment, one could evolve the cancer into a trap. The more of these traps that we find the stronger is our ability to control the cancer. It seems we are approaching a knowledge level in which cancer has no viable counter-strategy.

Best Wishes, J 

 

Hexadecatrienoic acid (HTA) 16:3 (n-3) all-cis-7,10,13-hexadecatrienoic acid
α-Linolenic acid (ALA) 18:3 (n-3) all-cis-9,12,15-octadecatrienoic acid
Stearidonic acid (SDA) 18:4 (n-3) all-cis-6,9,12,15-octadecatetraenoic acid
Eicosatrienoic acid (ETE) 20:3 (n-3) all-cis-11,14,17-eicosatrienoic acid
Eicosatetraenoic acid (ETA) 20:4 (n-3) all-cis-8,11,14,17-eicosatetraenoic acid
Eicosapentaenoic acid (EPA) 20:5 (n-3) all-cis-5,8,11,14,17-eicosapentaenoic acid
Heneicosapentaenoic acid (HPA) 21:5 (n-3) all-cis-6,9,12,15,18-heneicosapentaenoic acid
Docosapentaenoic acid (DPA),
Clupanodonic acid
22:5 (n-3) all-cis-7,10,13,16,19-docosapentaenoic acid
Docosahexaenoic acid (DHA) 22:6 (n-3) all-cis-4,7,10,13,16,19-docosahexaenoic acid
Tetracosapentaenoic acid 24:5 (n-3) all-cis-9,12,15,18,21-tetracosapentaenoic acid
Tetracosahexaenoic acid (Nisinic acid) 24:6 (n-3) all-cis-6,9,12,15,18,21-tetracosahexaenoic acid

 

 


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Daniel
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@jcancom Hi J,

Thank you for the list and nice to hear from you, like always.

Once, we should organize a meeting with Manuel and other friends around 🙂

We can discuss all the things we have learned over the years since we started to first discuss 3BP in the Cancer Compass forum, about 7 years ago .... btw, we should celebrate that somehow ... maybe with a new post on 3BP or metabolic inhibitors in general? 🙂

It's amazing that after all this time, metabolic inhibitors are still not mainstream. Have you seen the news about 2DG in India?

We are conducting a clinical trial in India, in a conventional hospital, and the doctors there have started to implement 2DG not only in oncology patients but also Corona. And the results were great! Some weeks ago we had a call from a doctor from India soooo happy that they started to save lives with 2DG. One man with oxygen levels in the range of 45 (yes crazy) got his oxygen to 70 in about 5 minutes after applying 2DG!

Actually prof Lampidis asked me to publish on Cancer Treatments one article on 2DG and Corona many months ago, but I did not have the chance to do that. 

The point is that metabolic inhibitors are great tools and can save lives both in Oncology filed and other area where metabolism is key (where not?).

Kind regards,
Daniel

 


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Jcancom
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D, that is impressive! Non-Western nations clearly are now the innovation leaders in medicine. It has been so disappointing to see a complete lack of willingness to investigate new treatment approaches in cancer (especially metabolic ones). Most of the clinical leadership for 3-BP has occurred outside of Western mainstream medicine.   

COVID has underlined how much Western medicine has abandoned empirical science. The example that you gave of an almost immediate response to 2-DG highlights a lack of commitment to observational learnings.

D, Corona shows the terrific power of metabolics when resistance is not involved. Without the disease fighting back, patients can receive a large benefit. The problem that we face with cancer is that after round 1 the cancer regroups for another round and another. This is why we have building up the knowledge base over all of these years; we need to have multiple rounds of treatment to respond to cancer resistance.  

A resource such as this forum is of great value to all those struggling with cancer as trying to piece all of this together while caring for or coping with cancer would be much too much. There is an enormous amount of research to try and process and we have only been able to extract a tiny fraction of the total of this research. I am always waiting for that next insight that will push us past the line. I will be very interested in any summary that you might create for all of our efforts.

 


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Jcancom
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Another metabolic? We have often discussed proton pump inhibitors (PPI) on forum. It had never occurred to me that PPIs are highly related to the metabolic perspective: proton pumps are what power mitochondrial OXPHOS! Clearly, this is highly central to metabolics. I had thought that PPIs might be more limited to the cell membrane more than the mitochondria.

Well, if PPIs are directed to the mitochondrial energy supply through OXPHOS that is highly interesting. One might imagine inhibiting the OXHPOS complexes and the proton pumps for added effect. this might be a particularly opportune time to try a formulation (such as chitosan) to direct the treatment directly to the cancer cells, as there can be problems when giving PPIs to all cells (they have a certain toxicity through long term use to mitochondria).

 


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Daniel
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@jcancom Very good point J. 

They do act on lysosomes and as a result they are interfering with autophagy https://pubmed.ncbi.nlm.nih.gov/23478938/  

Along the line of your thoughts, this is interesting: 

Proton pumps are also important in the transport of various substances in the body, as we will see in detail in later sections. And while proton pump inhibitors are designed to interact specifically with the hydrogen/potassium pump in parietal cells of the stomach, research suggests that they likely have nonspecific binding capabilities (3). In other words, their chemical structure enables them to bind to other proton pumps as well. Though PPIs don’t stay in the blood for very long, their binding to proton pumps is essentially irreversible—they will continue to inhibit the proton pump until the master antioxidant glutathione is able to facilitate dissociation (4). https://kresserinstitute.com/dangers-proton-pump-inhibitors/

Glutathione inhibition should increase their effectiveness if that is desired.

We would need to understand what other PPIs they interact with besides their well known target.

Kind regards,
Daniel


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Jcancom
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D, I am not sure if I have this correct, though aren't the OXPHOS subunit themselves proton pumps? They could stop the H+ from being expelled from the mitochondrial matrix. Proton pump inhibitors are very widely prescribed medicines for stomach reflux disease.

I was also thinking about your recent imipramine post. In order for macropinocytosis the actin cytoskeleton needs to remodel. Doesn't fenbendazole interfere with actin? Might be an interesting combination.

 

https://www.nature.com/articles/cddis201067

https://www.frontiersin.org/articles/10.3389/fphar.2016.00452/full


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Jcancom
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Back in 2015, a mito formulation for 3-BP was published. Linking up TPP to 3-BP and thus dragging it into the mitochondria was shown to have large anti-cancer effects in cells. However, no in vivo was included in the article. I have been waiting to see what would happen if this were to go in vivo.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335358/

 

 

As we see here in the cell study, TPP 3-BP was 1-2 LOGS! more potent than 3-BP.

 

 

 

 

 

 

Now we have a new mito-3-BP formulation. This time they also included cancer stem cell targeting with HA and also treated with NIR laser. This one had very large anti-cancer effects. Usually in a well established cancer model even slowing down the growth of cancer is difficult; with this treatment, cancer volume began to decline with days of treatment. Selectively removing cancer stem cells essentially takes away the driving force of cancer growth. Cancer stem cells are what sustain cancer growth while the rest of the tumor bulk merely make up the mass of the cells. It is not clear to me how far the laser would penetrate into the tumor, nor how applicable this wold be to human patients. However, this is a very impressive result. 

This research reported that the mito-3-BP did not appear to be toxic to any of the organ systems of the mice.

PMID: 34990518


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Jcancom
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After posting the above formulations I went through the many other formulations of 3-BP that have been published over the last few years; I count ~17. It is quite impressive.

I then reviewed one of the first formulations-- beta-cyclodextrin. As can be seen below this formulation had very large anti-cancer effects in a pancreatic model.This is a highly powerful result. They injected the mice with the pancreatic cancer cells and then just systemically treated with beta-CD-3BP. This is what cancer treatment has always wanted to achieve! Simply inject the cancer treatment and let it find its target with minimal side-effects-- That's what happened! This represents near precision cancer treatment.

The procedure that they used to formulate the drug was extremely simply. 3-BP + beta cyclodextrin (in DI water) sonicate -- shake - freeze- lyophilized. Cyclodextrin is merely a circular form of glucose; when the CD arrives at the cancer site it dissolves due to the acidity; releasing the 3-BP. 

On the left below we see the control mice. They had massive tumors after 1 month. The mice on the right that were treated with b-CD-3BP had minimal tumors. The graph below shows that there was essentially no tumor growth after 1 month with the treatment.

What is also of interest is that there was no combination treatment given. One might expect that citrate cotreatment with 3-BP would amplify the results as has been seen in previous research, though this and other synergistic treatment was not attempted.   

This research was published in 2014, though it is still of substantial relevance today. While we have briefly mentioned this result on forum before, I do not think that it was highlighted enough. Even though it is a remarkably simple formulation-- it is also extremely powerful. This is one of the few 3-BP formulations that could target cancer cells anywhere in the body without the physical limitations of laser, ultrasound etc..

 

 

 

 

 

 


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Jcancom
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Sorry here is the url for the article on pubmed.

https://pubmed.ncbi.nlm.nih.gov/25326230/


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Daniel
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 @jcancom 

Thank you, J. Very interesting and simple formulation. This is what I would have tried several years "at home".

Kind regards,
Daniel


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Jcancom
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D, there is so much cancer research that we have reviewed over the years and it is difficult to put it all together, though the Beta-cyclodextrin- 3-BP treatment appears to be a very very strong one. It has taken us so many years to think the many potential ideas, though this one would seem to be one of the strongest.

I think that we talked about this one on the cancer compass soon after it was published. From what I remember there was some resentment at how they made straight 3-BP appear toxic. This had not seen with the original research, though one could well imagine that they chose the dose just high enough so that 3-BP would seem toxic without the cyclodextrin. In the study they injected 5 mg/kg bare 3-BP which would be expected to cause considerable toxicity and it did.  

Even still, we have seen how injecting bare 3-BP can cause vein irritation. This is as expected as 3-BP can produce HBr which is a strong acid. Using the cyclodextrin formulation would be a reasonable way to increase patient comfort to avoid such vein problems. Also the cyclodextrin formulation would tend to further concentrate the 3-BP in the tumor environment which would also be a win for the patient. 

beta-cyclodextrin 3-BP might be one of the best treatments that could be placed near the top of a treatment program. As can be seen above in the figure on the right, even monotherapy with this approach yields massive tumor reduction. Remember with Jess, Gemcitabine was placed as the central treatment and then everything was just added on top of that. This did have a powerful anti-cancer effect (yet much of this power actually appears to have been related to the metabolic add-ons that Jess treated with including 3-BP), though depending on chemo locks you into roller coaster in which eventually the cancer will enter an uncontrollable growth stage even with side effects along the way. Patients can misinterpret the decline in tumor markers as real progress against the cancer, when in fact it is mostly just a futile process of selecting those cancer cells that are chemo resistant. Oncologists that can avoid chemotherapy clearly have a great deal of treatment expertise.

As we see in the middle picture above, Gemcitabine monotherapy had minimal anti-cancer effect in the pancreatic model. You really need a top treatment that you can work around, yet chemotherapy itself  offer low treatment power. If you want to move away from the standard of surgery, chemotherapy and radiation, then you need a powerful top line treatment. The above figure suggests that beta-cyclodextrin 3-BP could be such a treatment.

As soon as you have this powerful top line metabolic treatment, there are so many cotreatments that you could consider. With 3-BP, citrate, curcumin, methyl jasmonate, DCA, Fenbendazole, silver nanoparticles, oncolytic viruses, genistein, methylglyoxal, ketogenic diet, paracetamol etc. would then all have potential to amplify the response. Remarkably, in the above research, they did not even bother pursuing such combinations as the monotherapy itself had such a strong showing.

I was somewhat disappointed, though, when reading through the b-CD-3BP patent to find that the apparent intention is to combine with radiation and standard chemotherapy. It would seem more powerful to chart out a new pure metabolic treatment approach. I was surprised when I read the 3-BP citrate combination research that synergy can happen simply by double inhibiting glycolysis with the citrate. Merely inhibiting glycolysis at another glycolytic enzyme with citrate greatly enhanced the treatment power of 3-BP. As noted above several other metabolic inhibitors apparently have the same effect. One really wonders why it would be thought relevant to bring in standard chemo with all of its side-effects when double or triple metabolic inhibition might be free of such complications. This would need to be worked through, once the top line b-CD-3BP were available, then an entire ecosystem of parallel metabolics could emerge.

 

Below is additional results from the above research article. Here we can see the results for caspase-3, MCT-1 and GAPDH for B-CD control, gemcitabine and B-CD-3BP. These figures are quite startling.

The B-CD control on top had a near absence of caspase-3 activity, while having robust MCT1 and GAPDH expression. The tumor as can be seen is simply massive.

The gemcitabine treated mouse only has somewhat activated caspase-3 and reduced MCT-1 and GAPDH expression in comparison to the B-cD control. The 3 B-CD-3BP mice below show enormous caspase-3 activity and minimal activity of MCT-1 and GAPDH. It appears from the H&E column that much of the tumor mass in the B-CD-3BP mice had become a liquified necrotic mass so the expression analysis needed to choose those areas that had not underwent complete metabolic collapse. The one mouse in the middle of the B-CD-3BP group had a somewhat largish tumor mass, though it appears that they might have specifically selected this mouse for analysis as it had the most of any of these mice as seen in the figure above. With the B-CD control and gemcitabine treated mice, all of them appeared to have very large tumor masses.  

What is also of interest is that the next combinations to extend the metabolic collapse for the B-CD3-BP mice would seem obvious. The middle mouse still had some MCT-1 expression, so the initial round of 3-BP was not quite enough. We saw that with the melanoma patient, paracetamol can dramatically enhance the anti-cancer effect of 3-BP. Paracetamol knocks down GSH which acts to block the effects of 3-BP. Removing such a blocker can result in a profound combination effect. Other approaches including OXHPOS inhibition, additional glycolytic inhibition etc. could also amplify the effects beyond monotherapy B-CD-3BP.  

From this base, additional approaches that we have explored on the forum could be applied to weaken cancer from additional angles. What is of particular interest with the initial B-CD-3BP idea is that one would have greatly constrained the metabolic character of the surviving cancer cells. As can be seen below, there is dramatic selection against MCT-1 expression. The article found this to be an unexpected result, however, given the power of 3-BP, it would seem not that unexpected that there would be a dramatic selection against MCT-1 expression. The only cancer cells that could survive would be those without MCT-1 expression. 3-BP would remove all those cancer cells that did express it. This would create an interesting cancer phenotype: namely, the remaining cells would likely be highly constrained in their lactate production. This would be a great win! Lactate causes so many problems! Without an abundance of lactate many good things could happen-- e.g., less metastatic potential, inhibit the reverse Warburg effect, allow for the immune system to respond better against the cancer cells, reduced acidity, ... . Metabolic treatment would create a highly defined change in the cancer environment that would be common for a range of cancer types without reference to the complexities of the internal workings of specific mutations etc of individual cancer cells. Potentially this would allow for a rational metabolic treatment program that would be applicable to cancer in general (instead of trying to treat cancer as idiosyncratic instances). 

It is so discouraging that after all of these years a metabolic approach along the lines that we have discussed for so many years on forum has not emerged. It seems so immoral that patients continue to experience the typical treatment response with gemcitabine as shown above and not that of B-CD-3BP.         

 

 

 

 


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