https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase
https://pubmed.ncbi.nlm.nih.gov/27384481/
Absolutely amazing, metabolic is everywhere! Everywhere! I wonder whether cancer faces a problem with all the extra NADH? I mean what could it do with all of this NADH without a linked carbon source to expel? With glucose, you have glucose --> lactate NAD --> NADH --> NAD. Everything balances.
I wonder whether with aldehydes you generate NADH, though then what? This is surely what we see from the above article. Shutting down OXPHOS with phenformin creates a metabolic crisis!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226516/
It is just so exciting that we have another potential synergistic metabolic treatment. This one combining Aldehyde dehydrogenase and OXPHOS subunit 1. We have focused most of our attention on glycolysis and OXPHOS subunit 1, though other vulnerabilities appear to exist. The specific combination they mention is gossypol (ADLH1L1) and phenformin (OXHPHOS subunit 1). 2/7 of the mice above had a large response to this combo. Very recently a new chitosan formulation of gossypol was reported. Considering that cancer cells downregulate glycolysis at night (as I noted on a recent forum post), then nighttime dosing of the OXPHOS subunit 1 inhibitor might be worth considering.
This also has been wondering about somatic and tumor genetics. The cost of whole genome sequencing is rapidly falling and is expected to reach ~$100 per genome by the end of this year. This could have revolutionary importance for cancer medicine. Up till now we have recommended treatments largely blindly. We do not truly know which of a near infinite number of treatments might be the most beneficial. The age of tumor genomes could dramatically change that. With a tumor genome in hand, you could look and see the tumor genotype of MCT1, HK2, ALDH1L1, SLC31, SLC2A1 ... . This reasonably should have profound effects on treatment results.
Much of the published pre-clinical cancer research has large responses in ~20% of mice. However, if circulating tumor cells were genome sequenced, there would then be no reason why large responses could not occur in 100% of selected mice. It is very unclear to me why the research has not already adjusted to reflect this. There is an implicit distortion that there is some great mystery as to which mice will and will not respond: there isn't.
Genomically informed cancer therapy should be very powerful and effective. Please post comments that describe the current state of the art.
https://en.wikipedia.org/wiki/Aldehyde_dehydrogenase
https://pubmed.ncbi.nlm.nih.gov/27384481/
Absolutely amazing, metabolic is everywhere! Everywhere! I wonder whether cancer faces a problem with all the extra NADH? I mean what could it do with all of this NADH without a linked carbon source to expel? With glucose, you have glucose --> lactate NAD --> NADH --> NAD. Everything balances.
I wonder whether with aldehydes you generate NADH, though then what? This is surely what we see from the above article. Shutting down OXPHOS with phenformin creates a metabolic crisis!
HI J,
Thank you. I just want to let you know that asap I will look in to this and let you know my opinion.
Have a very nice weekend you and everyone who read this.
Kind regards,
Daniel
Yes, it is shameful. I only noticed after posting this one that you were on it a few years ago. Still I think some of these metabolic therapies that demonstrate substantial effects (admittedly in mice) need to be highlighted in their own threads. It would be another shot on goal. As the mice show only about 25% of them had large responses, yet that is not bad odds. Especially if you take 4 shots on goal all with 25% odds. It would be even better if we could genotype the tumor and move the odds essentially to 100%.
I looked at a family members ALDH1L1 genotypes. 5 out of 6! It is not entirely clear to me how this works. These SNPs increase cancer risk but decrease ALDH1L1 gene expression? So, the gossypol and phenformin combo would work better with this genotype? If we can start thinking in this way it might be able to help those on forum. Even knowing the somatic genotype would give you an idea of the safety of different treatment approaches. E.g., someone who had a natural genotype that always had MCT-1 open might not be a good candidate for 3-BP. This idea has already been applied to vitamin C treatment in screening out those with glucose-6-phosphate- dehyrogenase deficiency. Testing patients before treatment for G6PD makes a great deal of sense.
"Common SNPs at the polymorphic loci rs3796191, rs2886059, rs9282691, rs2276724, rs1127717, and rs4646750 in ALDH1L1 exons characterize more than 97% of Europeans while additional common variants are found in other ethnic populations. The effects of these SNPs on the enzyme is not clear but studies indicate that some coding and non-coding ALDH1L1 SNPs are associated with altered risk of certain cancer types and it is also likely that specific haplotypes define the metabolic response to dietary folate." https://www.frontiersin.org/articles/10.3389/fgene.2019.01013/full
D, it was funny I was reading around about this one and an article retorted that it wasn't so much NADH as NADPH. ALDH1L1 apparently has a much greater affinity for NADPH. Might be one of the often examples where explaining why is much more difficult than simply stating what.
ALDH1L1 opens up a whole new pathway to explore. We have focused so much on the mainline glycolysis and OXPHOS while not looking around further afield. The ALDs (there are 19 of them) could be especially important, though, as they appear to be related to cancer stem cells.
Another one that this started me thinking about was gluconeogenesis (GG). Gluconeogenesis, occurring mostly in the liver, is the reverse of glycolysis, it makes glucose! What caught my eye is that the main substrate for GG is lactate. Basically you can reverse glycolysis and burn through lactate. That sounds very useful. Lactate is one of the main systematic toxins that cancer produces. It causes a great many problems. What if you could simply tell the body to metabolize this toxin? Glucagon tells the body to start up GG. Wonder if it could be that simple?
https://www.sciencedirect.com/science/article/pii/S0304419X19301593
I really like these metabolic diagrams. They can express in one figure what could take pages of text. I think we should have an entire dedicated thread to posting these figures. Perhaps we can assemble them here and then port them over to a thread once we have accumulated a few. Above is citrate. So, yes it is quite clear that citrate could have powerful anti-cancer effects; it also makes a great deal of sense. Citrate is the first element in the traditional Krebs cycle, so the body needed ways of regulating citrate. It is clearly reasonable that when there is too much citrate in the mitochondria that you want the body to shut down other pathways such as glycolysis. Would be a good time to also shut down OXPHOS. 3-Bp had a powerful synergism with citrate. Another important point in the metabolic system that can be manipulated for potential treatment effect. As we have seen on the citrate threads there has been a fair amount of transfer to human treatment.
https://www.nature.com/articles/nrc2817
This is another great one that D has posted to his DCA page. The figure is not totally clear though about DCA. Near the bottom they show DCA blocking off PDK which then blocks PDH. The effect is not clearly shown on this diagram, though what then happens is that pyruvate is unblocked from entering the mitochondria, this down regulates glycolysis. NADH is not recycled to NAD+. OXPHOS is activated.
These digrams really are a very helpful way of understanding how treatments fit in to the overall metabolic landscape and suggest combinations that would be helpful.
https://clincancerres.aacrjournals.org/content/24/11/2482
Article has a very nice figure that shows how inhibiting OXPHOs can help reoxygenate hypoxic tumors. That can be helpful as oxygenation would allow for a range of helpful tumor responses to occur.
I would like to see methylglyoxal in one of these figures as it has been reported to be a specific OXPHOS I inhibitor. I am interested to see exactly and precisely what methylglyoxal actually interacts with in OXPHOS I.
This one does not want to behave properly. It is super big; too big. What I want to show here is the pro-metastatic effect of mito-fission vs fussion. Yet, there are dietary protocols that have been developed to promote fussion. See longecity for an extensive thread.
Sorry everyone this is another nice one. It shows how glycolysis and Krebs link up. It clearly shows how, shifting pyruvate from lactate to oxaloacetate/acetyl CoA stops the recycling of NADH back to NAD+, while producing yet more NADH (pyruvate dehydrogenase) or use up even more ATP (pyruvate carboxylase). The benefits of DCA can then be seen even more clearly.
https://www.mdpi.com/1422-0067/21/9/3363/htm
Same source as the above figure. This one adds in the novel idea of heme as a possible metabolic target. Article reports on the carniogenic effects of heme from the diet. Heme is a central molecule of OXPHOS. Article speaks of critical role of heme in lung cancer; SLC48A1 is the transporter for heme.
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-019-0678-9
Whoa! This is a big one! Viruses --> metabolically reprogram cells --> cancer?
Metabolics it really is everywhere! It's everywhere! So many times I have read articles and they try and create some convoluted non-metabolic path to an effect, when simply going directly to a metabolic explanation would make so much more sense. Basically, everything is metabolic until proven otherwise. The questions to always be asking are: How will this affect gycolysis? OXPHOS? ATP production? NADH? These are the fundamental mechanisms that drive cancer everything else is epiphenomenal.
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302548/
The syrosingopine metformin combination is also clearly impressive.My first post to the syro thread continues to resonate with me: stopping NADH recycling would have profound anti-cancer effects.
A genetic test that could prospectively find the responders would be so powerful. Perhaps those with genetic mutations in OXPHOS 1 or MCT-1 high expressers. One issue that could be of considerable help here is a better formulation of syrosingopine. The limitation of dosing due to the side effects could be overcome by perhaps a chitosan formulaiton, we have had access to the researchers so it would be helpful to ask about this. Typically OKish formulaitons such as even chitosan gets you down to a dose at least 100 fold (often ~500 fold) lower than non-formulated chemicals. That would be so helpful for syrosingopine as it has a range of side effects due to blood pressure lowering etc.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137433/
This is for single agent treatment with mito-honokiol. The patent holders amplified this with co-treatment with 2-DG (many others possible).
https://www.aging-us.com/article/101905/text
There are quite a few fans on forum for this vitamin C variant.
Synergistic eradication of cancer stem cells with triple combination: vitamin C, low doses of 2 antibiotics ( doxycycline and azithromycin. Very potent inhibition of cancer stem cells. These cells not the bulk of the tumor mass are what drive cancer progression. Is there a biomarker for cscs? People will often focus on the overall tumor mass without considering how important the CSCs are. They use low dose vitamin C (250 micromol). would high dose be better? Perhaps 25 millimol?
I am not sure about this one, though many of the treatments listed are familiar; all FDA approved.
https://atavisticchemotherapy.com
https://clinicaltrials.gov/ct2/show/NCT02366884
Drug: Anti-Bacterial Agents
Drug: Anti-Fungal Agents
Drug: Anti-Protozoal Agents
I hope others find having all of these figures in one place as useful as I do. It allows so many of the ideas of the forum to be concentrated, contrasted and compared. Here is the Warburg trap idea; an ingenious idea. Lock in the acid and then drain out the ATP in cancer cells. OXPHOS I inhibitors are found to raise intracellular pH. This strategy is then coupled with Wnt repression for even more cancer cell stress.
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I am sorry everyone I must say it again Wow, everything is metabolic! This one is really quite startling. The comparison that they make is the morphine is to heroin so is 2-DG to WP1122. 100 fold enhancement? Very startling.
Can it get better than this? Yes, yes it can. "the authors reported that blocking glycolysis with non-toxic concentrations of 2-DG completely prevented SARS-CoV–2 replication in human cells" https://www.moleculin.com/covid-19/ But human cells are in vitro, not in vivo. WP1122 allows the benefits of 2-DG in vivo. There is now a hurry to move WP1122 into human trials for COVID. The mechanism of action here is highly related to cancer metabolism. Viruses as noted in a previous post induce high levels of glycolytic stress. Yeah!
Observers of cancer research will notice that through time there are waves of enthusiasm for specific themes only to be replaced by a new theme a few years later. These themes help to orientate people's awareness into a certain "theory" of cancer. It would not be unfair to suggest that at this time "immunology" is now the dominant theme for cancer. If I were try to be more current I would probably be saying Wow, it's all immunity. What I find interesting given my comments above about viruses and metabolism in cancer is that the slides in the url could easily be re-imagined as part of a metabolic strategy. The reovirus would preferentially replicate in the tumor cells and quite likely place a large metabolic stress on the cancer cells. Pre-treating with metabolic stress ( perhaps metronomic 2-DG (WP11222?) etc.) might then make a fair amount of stress. And reovirus can only replicate in cancer cells so it would be highly specific to cancer.
@jcancom J, your point are again spot on. I have an article that Prof. Lampidis wrote and asked me if I can post but did not had the chance yet, addressing exactly this area. There is a new Nature paper exactly on 2DG against COVID. I think published by a German group. Prof. Lampidis speaks for long time about the role of 2DG in cancer and viruses, related to ER stress, leading to up-regulations of metabolic pathways. The same is what our guest from the largest cancer centre in Germany was speaking about in one of the earlier Blog posts I published. So whether we like it or not, metabolism stands out in both oncology and viral infections.
On this line, your idea to use viruses in combo with metabolic stress is perfect. Just make sure the viruses are the kind that induce ER stress. Next add extra drugs that induce ER stress and metabolic inhibitors, and you may have the perfect solution. I never thought about this idea and is perfect! It's obvious when you think about it but everything is simple after we know it. 🙂 Thanks for that. No, we would need to search for viruses that induce ER stress and that selectively infect tumors - we should be able to find them and I already have in mind a doctor in Germany who may have access to them.
Kind regards,
Daniel
@jcancom lets make a list of various such viruses that have been already used in humans, when we find the time. Thank you.
Very exciting D. This is from the moleculin website.
"The Short Version
- Viruses (like SARS-CoV-2) depend on glycolysis and glycosylation for infectivity and replication.
- Glycolysis and glycosylation can be disrupted by using a glucose decoy known as 2-DG.
- And, while 2-DG has been shown to be effective in vitro, 2-DG’s lack of drug-like properties makes it ineffective as a drug in humans.
- WP1122 has the potential to solve 2-DG’s problem by creating a prodrug of 2-DG that reaches much higher tissue/organ concentrations than 2-DG alone.
- We are moving as quickly as possible to prepare WP1122 for clinical evaluation in the treatment of COVID-19.
The Slightly Longer Version
Moleculin has a unique opportunity to contribute to the global challenge posed by coronavirus and other viruses threatening our communities. We recently announced a collaboration with a major Texas university institution to evaluate our drug candidate, WP1122, and its analogs and this has now been followed by collaborations with additional players who bring the needed expertise to fully develop this new potential treatment for diseases like COVID-19.
Independent researchers at the Institute of Biochemistry II – Goethe-Universität Frankfurt in Germany recently announced their discovery that 2-DG, the active compound in WP1122, reduced in vitro replication of SARS-CoV-2 by 100%.
We now have a very strong reason to believe that WP1122 may be effective against COVID-19. This is based on the vital roles that glucose plays in the proliferation of SARS-CoV-2. Viruses like SARS-CoV-2 place increased demand on glucose and upregulate their host cell’s metabolic processes. Some of the most important of these processes are believed to be glycolysis and glycosylation.
Given the roles of both glycosylation and glycolysis, it becomes apparent why glucose is critically important to the coronavirus. Given how important glucose is to these vital processes, one potential strategy for attacking viruses is to use their dependence upon glucose against them. And, this is where 2-DG comes in. 2-DG stands for 2-Deoxy-D-Glucose and it is referred to as a glucose decoy. To cells, 2-DG looks like glucose, but it has one of the hydroxyl groups (the OH symbol shown here in red) found in the chemical structure of natural glucose removed. This missing hydroxyl group is just enough of a change that 2-DG won’t actually convert into energy or support proper glycosylation.
Importantly, multiple independent studies have shown the disruption of both glycolysis and glycosylation, can have a potent effect against viruses like coronavirus.2, 3, 4, 5, 6, 7 This was, in fact, demonstrated in vitro in a range of viruses. These include rhinovirus, herpes and others, as well as porcine epidemic diarrhea virus, which is another coronavirus.
Very recently, researchers in Frankfurt, Germany, demonstrated the effect 2-DG has on SARS-CoV-2. In an unreviewed article recently submitted to NatureResearch ( https://www.researchsquare.com/article/rs-17218/v1 ) .... "
Probably should stop it at that. Much more and it would be copywrite infringement.
D, this is super exciting! With cancer everything takes forever. Even if they had the cure in hand now it would take years and years to think about and finally authorize it. But with COVID ... the entire game changes ... life has stopped ... the children do not go to school ... money cannot be made ... COVID it must be solved NOW! If it isn't ... trouble. Yet, as we can see the funny thing here is that COVID and cancer have a lot more in common than I would have believed before my recent posts. I was highly unaware how much viruses are really a parallel pathology to cancer. Something like a cancer specific virus such as reovirus could be highly useful as a metabolic treatment. Yes, it's true metabolics is everywhere. Add in some 2-DG and you really start to wonder: how much more energy stress could the cancer cells take? With the oncolytic virus, the virus can only replicate in the cancer cells-- it's highly specific. It is fairly amusing though that the entire writeup for reovirus is in relation the immune system, to immunotherapy. D, I could never work like that. Everyone is singing from the same song sheet. With cancer it isn't reasonable to think that there is only one dogmatically doctrinaire truth.
I do wonder about the figure above. 2-DG changes an hydroxyl group on the bottom right. What might happen if another of the groups around glucose were changed? Might this have an even moer powerful anti-cancer effect?
D, remember how we spoke about the Australian rabbit virus? Seems quite effective in vivo.
An oncolytic virus has been FDA approved for melanoma: Imlygic (talimogene laherparepvec, or T-VEC). I wonder whether metabolic co-treatment would help?
I have also been reading up on chitosan and so called mannosylation and how this can deliver DNA etc to immune cells. Would be interesting if this too could be used to amplify the oncolytic effect.
https://www.oncolyticsbiotech.com/technology
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098891/pdf/BMRI2014-526391.pdf
Adding in the viruses as another layer of metabolic stress is actually quite impressive as you noted. At a certain point the cancer cells would simply be overwhelmed. What is especially important is that oncolytic viruses can only replicate inside of the cancer cells. This is completely cancer specific. Added to OXHPOS inhibitors, 2-DG etc., the metabolic stress begins to appear quite formidable.
That's actually funny, I am not sure if this has been suggested on the forum, but what if corona virus is actually oncolytic? Perhaps then WP1122 would be ready to completely control the virus if this became necessary.
Could you advance the name of that doctor? The administration of the virus would be intratumoral or by afferent vein ?
@marcosbomber901 Sure Marcos. I will send the name by e-mail. For practical questions you can ask Steffen. (I think they apply on the tumor, locally.) He is going with his wife often for the treatment. Kind regards, Daniel
Oncospecific viruses open up a powerful new line of metabolic weakness of cancer cells. The entire genetic program encoded in viral DNA is directed at metabolic disturbance of cells. It is disappointing that we had not thought of this before. That's what happens when you aren't fully converted to the metabolic perspective: metabolics can be right in front of you and you do not even realize it.
Just like Newton; he didn't realize that there was gravity until he got bonked on the head with the apple. I wouldn't even be that surprised that it took more than one apple. Perhaps he needed bed rest for a week or two and then discovered gravity.
So, the virus enters the cancer cell and it then goes about hijacking the metabolic machinery of the cell. It needs energy, building blocks, etc.. It needs to be a parasite of the cancer cell, just as cancer is a parasite of the body: yet, the design of viruses means that they can be even better parasites than cancer. All of the processes that the virus needs to access are central metabolic processes that we discuss here endlessly.
One idea that I am now considering is whether there is a necessity to think in terms of destroying the cancer cells at all. This is the dominant mentality that now applies. Virus enters cells --> makes many copies of itself --> cancer cell bursts. What I found interesting is the idea that perhaps what might be an even better idea is to simply normalize the cancer cell biology.
The motivation lies in the realization that in a tumor of size ~1 cm3 a great deal of cancer cell destruction would be required. If the destruction were not complete, then the cancer might then emerge elsewhere in the body. What if instead of trying to destroy the 1 cm3 one simply chose to "bandage" the tumor? That is one could normalize the metabolism of the outer layer of the cancer cells. Here one might have 1 cm2 tumor area and now one might only need to normalize a layer of ~ 0.1 -1 millimeters a total volume (~0.1 cm3) an order of magnitude or more less than the entire tumor. This has been shown to be a very powerful strategy in other treatments (e.g., with angiogenesis blocking). All you need to do is control strategically important locations in the cancer environment without going to the effort of much unnecessary destruction. Once you have achieved control of the high ground you have enormous leverage to control everything downstream. For example, the cells on the blood vessel side would have first access to nutrients, oxygen etc. from the bloodstream. Controlling the high ground would mean that you could remove the supply lines for the rest of the tumor.
Basically, all that is needed is to put a cover on the tumor (normalize the outer layer) and then the rest of the tumor could be placed under a great deal of stress. For example, what if an oncospecific virus could normalize the lactate production on the outer layer of the tumor? Would this not help to seal in the lactate farther in the tumor? Normalizing lactate in this way could be very helpful. Perhaps an enzyme could be inserted into the virus that would produce oxygen. This could also be a very helpful adjustment that could help to normalize the cancer environment.
Unfortunately, I have not seen any applications of metabolic thinking in the current generation of cancer viruses. Almost without exception everyone is thinking in terms of immunology not metabolism.
This is an exciting one. It helps to enhance our understanding of how cancer cells can escape from glucose limiting situations. The metabolic theory of cancer has an implicit assumption that glucose withdrawal will lead to an energy crisis. This assumption would seem almost a logical tautology. However, article found that in some resistant cancer cells, Ca2+ influx with PP2Ac demethylation and subsequent cell destruction was prevented by glucose/2DG. Interestingly, the glucose analog 6-DG did not have a similar anti-destruction effect.
This newly cancer destruction pathway could become yet another tool to block off treatment resistance in metabolic therapy.
