A List of Mitochondria Inhibitors

When looking at cancer as a metabolic disease, mitochondria (the engine of the cell) plays a key role in tumor development (Ref.). As a result, mitochondria inhibitors are important tools to be included in an anticancer treatment strategy. There is vast amount of information available on the web on this subject, so I am not going to dive into the science of mitochondria and it’s relevance to cancer. For anyone looking for a deeper understanding of this, it could be good to start with the Nature Review paper cited above.

One example of a mitochondria inhibitor is CPI-613 (Ref.), currently developed by Rafael Pharmaceuticals (Ref.). This drug is currently in clinical trials for various cancers, including pancreatic cancer (Ref.). Following results from previous trials, mitochondria inhibition approach looks very promising. For example, in one clinical trial CPI-613 was used in combination with bendamustine in patients with T-Cell Lymphoma, and exhibited a very good signal of efficacy with an 86 per cent Objective Response Rate (43 per cent Complete Response and 43 per cent Partial Response). (Ref.).

Interestingly, the design of the trial in pancreatic cancer it’s not as I would expect. They give CPI-613 one day prior to chemotherapy (Ref.). However, as I discussed here (Ref.), it has been recently shown that mitochondria inhibitors are best given during the chemo day in order to increase chemo effectiveness, and in contrast to that, when given prior to chemo may lead to reduction of chemo effectiveness. (I will contact Rafael Pharmaceuticals and check that)

Nevertheless, mitochondria inhibitor alone may not be enough to kill tumors, but as visible from the clinical trial cited above, when combined with other therapies, such as chemotherapy, radiation (but also new therapies including glycolysis inhibitors such as 2-dg, 3-BP, etc.), the results may be very relevant.

We’ve had discussions on this website many times about the relevance of mitochondria inhibitor, so this subject may not be new for some. However, the results shown by CPI-613 are increasing our confidence in thsi approach, further supporting the need to consider mitochondria inhibitors when looking for a way to increase the chance of an effective treatment strategy.

Since CPI-613 is not yet available, the obvious next step is to search for other mito inhibitors that are both cheap and accessible. Here is a list of mitochondria inhibitors I am aware of:

  • Pyrvinium Pamoate, – FDA approved drug – cheap and available but low absorption in the human body
  • Meclizine, – FDA approved drug – cheap and available
  • Doxycycline, – FDA approved drug – cheap and available
  • Metformin (Ref.), – FDA approved drug – cheap and available
  • Atovaquone (Ref.), – FDA approved drug – cheap and available
  • Canagliflozin (Ref.) – FDA approved drug – cheap and available
  • Oligomicin (Ref.). – not approved – expensive, not safe and not easy to access
  • Troglitazone (Ref.) – FDA approved drug – cheap and available
  • Honokiol (Ref.). –  a natural substance – available as supplement online
  • Tigecycline (Ref.) – FDA approved drug – injectable
  • Niclosamide, Nitazoxanide, Closantel (Ref.) – FDA approved drugs
  • Perhexiline (Ref.1, Ref.2) – approved for use as an anti-angina agent in Asia, Australia and New Zealand

If you are aware of any other (strong enough) mitochondria inhibitors, please post a comment here.

Note:

  • combining mito inhibitors with glycolisis (fermentation) inhibitors makes sense since different cancer cell types may undergo different bioenergetic changes, some to more glycolytic and some to more oxidative.
  • in addition, using only mito inhibitors is expected to lead to an increase of the glycolisis and systemic acidity. Therefore, if mito inhibitors are used for longer time, it may be not only good but desirable to combine them with glycolisis inhibitors (such as 2DG, high dose Vitamin C, etc.) and proton pump inhibitors (such as discussed here)  and alkalizing supplements (such as Basentabs).
  • However, there is a potential problem when specifically combining Canaglifozin with 2DG. That is because the main function of Canaglifozin is to inhibit glucose transporters. (Mito inhibition is just an off target action for the drug.) That is why it is today used as an anti diabetic drug –> inhibition of some (but not all) glucose transporters (Ref.). And the problem is that this function may in turn reduce the 2DG absorption in the cancer cells. Therefore, I would avoid overlapping in time Canaglifozin with 2DG administration (Ref.).

Other References:

Mitochondrial metabolism and cancer https://www.nature.com/articles/cr2017155#ref172

Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioenergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents. However, tumors arise, progress, and respond to therapy in the context of an intimate crosstalk with the host immune system, and many immunological functions rely on intact mitochondrial metabolism. Here, we review the cancer cell-intrinsic and cell-extrinsic mechanisms through which mitochondria influence all steps of oncogenesis, with a focus on the therapeutic potential of targeting mitochondrial metabolism for cancer therapy.

Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. https://www.ncbi.nlm.nih.gov/pubmed/21769686

We report the analysis of CPI-613, the first member of a large set of analogs of lipoic acid (lipoate) we have investigated as potential anticancer agents. CPI-613 strongly disrupts mitochondrial metabolism, with selectivity for tumor cells in culture. This mitochondrial disruption includes activation of the well-characterized, lipoate-responsive regulatory phosphorylation of the E1α pyruvate dehydrogenase (PDH) subunit. This phosphorylation inactivates flux of glycolysis-derived carbon through this enzyme complex and implicates the PDH regulatory kinases (PDKs) as a possible drug target. Supporting this hypothesis, RNAi knockdown of the PDK protein levels substantially attenuates CPI-613 cancer cell killing. In both cell culture and in vivo tumor environments, the observed strong mitochondrial metabolic disruption is expected to significantly compromise cell survival. Consistent with this prediction, CPI-613 disruption of tumor mitochondrial metabolism is followed by efficient commitment to cell death by multiple, apparently redundant pathways, including apoptosis, in all tested cancer cell lines. Further, CPI-613 shows strong antitumor activity in vivo against human non-small cell lung and pancreatic cancers in xenograft models with low side-effect toxicity.

Therapeutic potential of CPI-613 for targeting tumorous mitochondrial energy metabolism and inhibiting autophagy in clear cell sarcoma.  https://www.ncbi.nlm.nih.gov/pubmed/29879220

Clear cell sarcoma (CCS) is an aggressive type of soft tissue tumor that is associated with high rates of metastasis. In the present study, we found that CPI-613, which targets tumorous mitochondrial energy metabolism, induced autophagosome formation followed by lysosome fusion in HS-MM CCS cells in vitro. Interestingly, CPI-613 along with chloroquine, which inhibits the fusion of autophagosomes with lysosomes, significantly induced necrosis of HS-MM CCS cell growth in vitro. Subsequently, we established a murine orthotropic metastatic model of CCS and evaluated the putative suppressive effect of a combination of CPI-613 and chloroquine on CCS progression. Injection of HS-MM into the aponeuroses of the thigh, the most frequently affected site in CCS, resulted in massive metastasis in SCID-beige mice. By contrast, intraperitoneal administration of CPI-613 (25 mg/kg) and chloroquine (50 mg/kg), two days a week for two weeks, significantly decreased tumor growth at the injection site and abolished metastasis. The present results imply the inhibitory effects of a combination of CPI-613 and chloroquine on the progression of CCS.

Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect. https://www.ncbi.nlm.nih.gov/pubmed/29445145

Recent FDA Drug Safety Communications report an increased risk for acute kidney injury in patients treated with the gliflozin class of sodium/glucose co-transport inhibitors indicated for treatment of type 2 diabetes mellitus. To identify a potential rationale for the latter, we used an in vitro human renal proximal tubule epithelial cell model system (RPTEC/TERT1), physiologically representing human renal proximal tubule function. A targeted metabolomics approach, contrasting gliflozins to inhibitors of central carbon metabolism and mitochondrial function, revealed a double mode of action for canagliflozin, but not for its analogs dapagliflozin and empagliflozin. Canagliflozin inhibited the glutamate dehydrogenase (GDH) and mitochondrial electron transport chain (ETC) complex I at clinically relevant concentrations. This dual inhibition specifically prevented replenishment of tricarboxylic acid cycle metabolites by glutamine (anaplerosis) and thus altered amino acid pools by increasing compensatory transamination reactions. Consequently, canagliflozin caused a characteristic intracellular accumulation of glutamine, glutamate and alanine in confluent, quiescent RPTEC/TERT1. Canagliflozin, but none of the classical ETC inhibitors, induced cytotoxicity at particularly low concentrations in proliferating RPTEC/TERT1, serving as model for proximal tubule regeneration in situ. This finding is testimony of the strong dependence of proliferating cells on glutamine anaplerosis via GDH. Our discovery of canagliflozin-mediated simultaneous inhibition of GDH and ETC complex I in renal cells at clinically relevant concentrations, and their particular susceptibility to necrotic cell death during proliferation, provides a mechanistic rationale for the adverse effects observed especially in patients with preexisting chronic kidney disease or previous kidney injury characterized by sustained regenerative tubular epithelial cell proliferation.

Troglitazone Stimulates Cancer Cell Uptake of 18F-FDG by Suppressing Mitochondrial Respiration and Augments Sensitivity to Glucose Restrictionhttps://www.ncbi.nlm.nih.gov/pubmed/26449833

We evaluated how troglitazone influences cancer cell glucose metabolism and uptake of (18)F-FDG, and we investigated its molecular mechanism and relation to the drug’s anticancer effect.

METHODS:
Human T47D breast and HCT116 colon cancer cells that had been treated with troglitazone were measured for (18)F-FDG uptake, lactate release, oxygen consumption rate, mitochondrial membrane potential, and intracellular reactive oxygen species. Viable cell content was measured by sulforhodamine-B assays.

RESULTS:
Treatment with 20 μM troglitazone for 1 h acutely increased (18)F-FDG uptake in multiple breast cancer cell lines, whereas HCT116 cells showed a delayed reaction. In T47D cells, the response occurred in a dose-dependent (threefold increase by 40 μΜ) manner independent of peroxisome proliferator-activated receptor-γ and was accompanied by a twofold increase of lactate production, consistent with enhanced glycolytic flux. Troglitazone-treated cells showed severe reductions of the oxygen consumption rate, indicating suppression of mitochondrial respiration, which was accompanied by significantly decreased mitochondrial membrane potential and increased concentration of reactive oxygen species. Troglitazone dose-dependently reduced T47D and HCT116 cell content, which was significantly potentiated by restriction of glucose availability. In T47D cells, cell reduction closely correlated with the magnitude of increase in relative (18)F-FDG uptake (r = 0.821, P = 0.001).

CONCLUSION:
Troglitazone stimulates cancer cell uptake of (18)F-FDG through a shift of metabolism toward glycolytic flux, likely as an adaptive response to impaired mitochondrial oxidative respiration.

Cancer stem cells (CSCs): metabolic strategies for their identification and eradication https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5941316/

Phenotypic and functional heterogeneity is one of the most relevant features of cancer cells within different tumor types and is responsible for treatment failure. Cancer stem cells (CSCs) are a population of cells with stem cell-like properties that are considered to be the root cause of tumor heterogeneity, because of their ability to generate the full repertoire of cancer cell types. Moreover, CSCs have been invoked as the main drivers of metastatic dissemination and therapeutic resistance. As such, targeting CSCs may be a useful strategy to improve the effectiveness of classical anticancer therapies. Recently, metabolism has been considered as a relevant player in CSC biology, and indeed, oncogenic alterations trigger the metabolite-driven dissemination of CSCs. More interestingly, the action of metabolic pathways in CSC maintenance might not be merely a consequence of genomic alterations. Indeed, certain metabotypic phenotypes may play a causative role in maintaining the stem traits, acting as an orchestrator of stemness. Here, we review the current studies on the metabolic features of CSCs, focusing on the biochemical energy pathways involved in CSC maintenance and propagation. We provide a detailed overview of the plastic metabolic behavior of CSCs in response to microenvironment changes, genetic aberrations, and pharmacological stressors. In addition, we describe the potential of comprehensive metabolic approaches to identify and selectively eradicate CSCs, together with the possibility to ‘force’ CSCs within certain metabolic dependences, in order to effectively target such metabolic biochemical inflexibilities. Finally, we focus on targeting mitochondria to halt CSC dissemination and effectively eradicate cancer.

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26 thoughts on “A List of Mitochondria Inhibitors

  1. Thank you Daniel for another brilliant article. I admire your selfless pursuit of collecting and sharing information, information that give hope and help to people suffering. What you do is truly meaningful.

    1. Thank you Carl for your continuous support. I haven’t had the chance lately to add much content as I was more focuss on a project relate to oncology wich seems to generate important response in various forms of cancer. I will write soon about that.

      1. Vitamin C has at least a dozen anti-cancer mechanisms: (1) AA stimulates H2O2 intracellularly, thereby destroying the cancer cell from the inside out, as cancer lacks catalase enzyme to neutralize it. (2) As a reducing agent may repair cancer’s dysfunctional self-destruct intracellular process and thereby allowing apoptosis to occur. (3) When converted to DHAA (in the production of H2O2 in the presence of metal ions) it is absorbed through the GLUT transporters is rapidly absorbed by cancer cells and not normal cells, and concentrates there. (4) Concentrated DHAA disrupts ATP production via the metabolic process I mentioned in the prior comment. (5) Extracellular DHAA competes with glucose for GLUT transporters to hasten the warburg effect. (6) Concentrated DHAA absorbs all reductase stores like GSH, thereby further restricting cancer energy utilization and the ability to self-repair. (7) Upon conversion back to AA within the cancer cell from the Fenton reaction it immediately cycles through that reaction to convert back to DHAA while creating even more H2O2 due to the overabundance of copper in cancer cells, causing more unmitigated redox damage from the inside out. (8) It converts homocysteine thiolactone (which is in large concentration in cancer compared to normal cells) to a toxic compound 3-mercapto. (9) Decreases HIF protein levels which decreases gene transcription. (10) Increases collagen synthesis resulting in decreased tumor invasion and metastasis. (11) Induces Tet-dependent DNA demethylation and a blastocyst-like state and induces epigenomic remodeling. (12) AA enhances the proliferation of NK cells, a group of cytotoxic innate lymphocytes, and enhances T cell proliferation and may influence T cell function. Of course I haven’t delved into the whole quality of life arguments for IVC, which in my personal opinion, are the strongest reasons why every cancer patient should be taking large doses of vitamin C at a minimum if they aren’t getting IVC.

        Let me know if you want citations

        1. Thank you for this. I like Vit C. But as you probably know, for many substances in this world we can colect a long list of various mechanism that may have been found in relation to that substance. What we are looking for is “the tip of the arrow” (major mechanisms) in terms of action for every substance. Following that, there may be multiple downstream mechanism taking place at various “intensity” levels since nearly everything is connected to some extend. This is key in identifying the value when doing research.

        2. lullabyman, welcome back to the forum!

          Your comments about duration dosing with vitamin C has been one of my high points in my cancer treatment quest. Cancer knowledge is so obscured that it can takes years and years to figure out truth from untruth. Your assistance in reveaIing the actual clinical experience with vitamin C and what might have potentiated these clinical experiences back in the 1970s is very much appreciated.

          I continue to find it highly impressive that 8% of the original patients (4 of 50) developed a fatal TLS response to
          vitamin C (Some even to a few grams of oral Vitamin C!). I do not see how the heated argument could have continued for almost half a century with these reports of TLS. Don’t people even bother with facts any more during a debate?

          There have been so many exciting developments over the last year (ox40/TLR9, all the 3-BP news, so much more!). I am waiting and hoping for a decisive breakthrough.

          I have been looking around for a nanoparticle for paracetamol. Specifically knocking down cancer cell GSH could be very handy. This is one important line of defence that cancer cells have against 3-BP etc.. We saw what happened with the melanoma patient when combo 3-BP paracetamol was given (LDH almost to zero.). Might you be aware of such research? Love to hear your comments.

          1. Yes, Cancer cell GSH is, I’m convinced, a significant rescue molecule for cancer cells when they’re on the edge of mitochondrial collapse. We’ve also seen it with IVC, cancer cell rescue by GSH. The same things that potentiate IVC might have a potentiating effect on 3-BP as well, if the IVC potentiation has anything to do with suppressing GSH stores. Two substances come to mind (powerful IVC potentiators): alpha lipoic acid, and vitamin K3 (controlled substance, sold as apatone(r)). There are a number of others but those 2 are perhaps the most effective.

  2. Might want to check this out … https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764395/. DPI (Diphenyleneiodonium chloride) selectively blocks mitochondrial respiration. “”At 10 nM, DPI inhibited oxidative mitochondrial metabolism (OXPHOS), reducing mitochondrial driven ATP production by >90%. This resulted in a purely glycolytic phenotype”… “DPI is ∼30 times more potent than Palbociclib (IC-50 = 100 nM), which is an FDA-approved CDK4/6 inhibitor, that broadly targets proliferation in any cell type, including CSCs.”

      1. No, it does look like it’s really in the early development stages, but interesting that it works by suppression the activity of riboflavin, which as the effect of preventing cancer from growing or mutating … a great way to keep cancer from becoming drug resistant.

    1. That was the question that I never seemed to ask but wanted to:

      Has paracetamol been used in iv vitamin C treatment?
      GSH appears to bind to almost any anti-cancer drug (including 3-BP) and in doing so neutralize its effectiveness.
      With the 3-BP melanoma patient it was only when they administered the combination 3-BP and paracetamol that the cancer
      cells nearly completely collapsed. A nanoformulation of paracetamol would be awesome!

      1. D, I think a great companion article to this one would be: A List of Glycolytic Inhibitors.
        If we are moving to metronomic 2-DG dosing it would likely be helpful to have a ready list of other anti-glycolytics.

        1. J, great idea. I will do it as soon as I can. Now fighting with my e-mail box, so I am in a reactive mode. If you like to start that, you are more than welcome, and I can publish an article as you the author, and I will add to that. Otherwise we need to wait until I find the time.

        2. D, I have an idea!

          Could you open up a new topic for the glycolytic inhibitors and then posters could post ideas about different anti-glycolytics.
          I am sure that you have a fairly extensive list of these inhibitors, though my list would be less comprehensive. Other posters could help fill in some of the gaps. Best Wishes, J

      2. I believe this is the reason why The treatment with 3-BP + Paracetamol was so effective: They inhibited glycolisis and decreased mitochondrial respiration at the same time.

        https://www.ncbi.nlm.nih.gov/pubmed/27085476
        Cardiolipin fatty acid remodeling regulates mitochondrial function by modifying the electron entry point in the respiratory chain.

        We have made the discovery that acetaminophen remodels CL fatty acids composition from tetralinoleoyl to linoleoyltrioleoyl-CL, a remodeling that is associated with decreased mitochondrial respiration. Our data show that CL remodeling causes a shift in electron entry from complex II to the β-oxidation electron transfer flavoprotein quinone oxidoreductase (ETF/QOR) pathway. These data demonstrate that electron entry in the respiratory chain is regulated by CL fatty acid composition and provide proof-of-concept that pharmacological intervention can be used to modify CL composition.

        1. Yud, the 3-BP research has found that it is more of a complexation of 3-BP and GSH that occurs.
          When the GSH is exhausted, 3-BP can without opposition deplete ATP, though there are a few other cell defences that are available.

          PMID: 28236852
          PMID: 27582536
          PMID: 26922560
          PMID: 26530987
          “Interestingly, the activity of both glyoxalase I and II, devoted to the elimination of the cytotoxic methylglyoxal, was strongly inhibited by 3-BP.” Hmmm, very interesting!
          PMID: 25196479

      3. This has not been tried, from what I can tell. It looks very exciting. Only recently have they looked into mitochondrial effects of paracetamol, but from what I can tell it looks like it would have a potentiating effect with intravenous vitamin c, on a number of levels.

        1. Whoa! This looks very exciting, I am not sure whether D covered this in his MG article.

          Apparently, MG is a SELECTIVE mitochondrial subunit 1 inhibitor. I had not fully appreciated this aspect of MG. 3-BP can give you a very good and specific hit against glycolysis, combining with MG could massively amplify the response. Research suggested that perhaps cardiac cells were also inhibited by MG, though they found that creatine selectively reversed this effect PMID: 16112157.

          Notice in Table 1 of PMID: 1995489 increasing MG and Ascorbic acid improved effectiveness of the combo a large amount. I certainly wonder why they would not have used more Ascorbic acid and in iv dosage. D mentioned an oral dose of Ascorbic acid of only 400 mg!

          The Methyglyoxal universe is starting to look very impressive!

          Metronomic dosing PMID: 30170097
          Selective OXPHOS inhibition at mitochondrail subunit 1 NADH PMID: 9163322 PMID: 12605598
          Nanoformulation combine with vitamin C, creatine etc, PMID: 25999714

          If we have a selective OXPHOS inhibitior what happens when we combine with a selective glycoslyis inhibitor?
          Say perhaps 3-BP? PMID: 26530987

          Even better put 3-BP into a nanoformulation: PMID: 29286239
          {Upgrade the formulation from this article to third generation tumor targeting peptides}
          Use same formulation technique to also cotreat with paracetamol.

          3-BP knocks down Glo1 and Glo2, which degrades MG, and depletes ATP.
          Vitamin C creates ROS which upregulates MCT-1.

          Cotreat with other 3-BP, paracetamol and other drugs filled into various nanoformulaitons including:
          PMID: 26185443 , PMID: 25326230, PMID: 29320411

          Load up second generation minicells which need no dual bispecific antibody attachment, merely add minicells to drug and allow loading. PMID: 29556350

          This is starting to appear to be an extremely powerful and specific treatment approach. Knocking out both OXPHOS and glycolysis using highly targeted nanoformulations could have immense treatment power.

        2. lullabyman, this is something that I have only lately become aware of: Most cancer treatments really should be thought of more as platforms that develop over the course of decades. So we have the vitamin C platform, the 3-BP platform, the MG platform. Whenever, I now hear someone say “well, I don’t think vitamin C (or 3-BP or MG etc.) is an effective anti-cancer therapy” my lie detector radar goes into full alert. It is not reasonable to say that a platform that has been developing over the course of 50 years or sometimes even more than a century is actually wrong.

          In fact what happens is that over the course of decades these platforms simply become stronger and stronger. I am quite impressed with how much progress the MG platform has made over the last 10 years. They have developed a nanoformulation, they have recently disclosed a metronomic dosing approach, etc. . What I would love to see next is an optimization of the vitamin C combo treatment (perhaps using co treatment of high dose iv vitamin C metronomic along side metronomic nanoMG). I would also like to see them up dose the nanoMG. In the research I cited they massively down dosed with nanoMG. If nanoMG is so non-toxic, why not move to higher dosing? Could also combine with CREKA tumor targeting liposomal MG. For the cherry on the top, combine with another selective anti-glycolytic such as 3-BP in a nanoformulation (possibly with paracetamol).

          It is very surprising to me that we have MG on the table which is a SELECTIVE OXPHOS inhibitor. I am not entirely sure if I could think of any other OXPHOS inhibitor is so highly selective as MG.

          D’s article did in fact mention the NADH selectivity of MG in the small print, though I think this needs to be put in the HEADLINES!!!

          MG can selectively target tumor OXPHOS!!!!
          This is big news!

          The cardiac OXPHOS targeting can be selectively reversed with creatine etc. . This is a truly shocking development. Lots of times you can knock down glycolysis or you can knock down OXPHOS in cancer cells, though you also knock down these energy pathways in normal cells. It is something special when you have an MG, or a vitamin C or a 3-BP and you specifically target the cancer’s energy supply. I would truly love to see the article that did this combo in lab models. The energy depletion should be truly profound! If you shut down glycolysis and OXPHOS at the same time? What then? How many minutes can cancer live with no energy supply?

          lullabyman, has there ever been a metronomic vitamin C study done? Should this metronomic treatment of iv vitamin C (starting with only monotherapy vitamin C) be safe? What cotreatments would be favored with metronomic iv vitamin C?

        3. J, you have found a very sympathetic ear here. I’m experiencing first-hand exactly what you’re talking about where those leading the charge for a certain therapy seem more interested in making it barely effective than maximally effective within tolerable dosing (which in fact might require something uncomfortable and inconvenient like an infusion of sorts). It’s pure insanity, and yet it seems so many researchers seem obsessed with the idea of minimizing dose to achieve marginal efficacy. I can only imagine they do it because at minimal doses perhaps efficacy can be realized by oral means, at a minimum mfg cost point, which translates into an oral drug that can be patented and sold for maximum return. I may sound jaded here, but not without good reason. I sympathize entirely with William F Koch … few, very few, especially among those who’ve found success, are willing to leave the cozy embrace of the environment from which they’ve found the comforts of wealth and esteem. This means they aim to make their art marginally better without taking the risks that might revolutionize medicine and thereby up-end the financial structure that supports the ecosystem in which they’ve learned to thrive. This holds as true within alternative medicine as it does in conventional medicine.

          Another thing worth noting in the MG and ascorbic acid study you identified… they used chewables for the vitamin C. From my experiences it is highly likely that most of the vitamin C in chewables is oxidized. Vitamin C is so incredibly fragile it doesn’t take much to rob it of one of it’s 2 bio-available electrons, easily done by pounding them into pills filled with sweeteners, fillers, and artificial colors. The oxidized state of vitamin C is incredibly compromised, and it no longer has the redox potential to jump-start the fenton reaction responsible for its anti-cancer properties. It’s the worst form of the vitamin C.

          Did you see those studies where vitamin C + doxycycline selectively killed CSCs better than anything to date? It used doxycycline for the OXPHOS inhibitor, but using MG … anyone can buy MG, don’t need to convince some doctor to get a prescription for it.

          Metronomic IVC has been done. It was done with I believe 24 patients about 25 years ago by the Riordan Clinic (back then it was called CIHFI) through the University of Nebraska and was published in a small Puerto Rican journal of medicine. They call it the “nebraska study”. It was shown to be very safe … no adverse events. It was done just to test the protocol for safety purposes, and was done on all refractory cancer patients, all who discontinued the therapy after 8 weeks when the trial ended, except for one patient who continued it for 2 years because he found it so beneficial. All patients saw all of their cancer markers improve during that time, but their disease progressed so it wasn’t a slam dunk. But there are a lot of things about the study we don’t know … I doubt for example that the solution wasn’t oxidized. And they were likely all bed ridden the whole time. The very first time this kind of study (continuous IVC) was done was in the 70’s … the very first tests with IVC were done in a semi-continuous fashion by Ewing Cameron and Linus Pauling. They saw on average a 4X life expectancy improvement, across 150 patients. The test was repeated in Japan where they saw similar results with the same sample size. Soon after that they went to large bolus dosing (up to 100g over 3 hours), presumably to save costs, and it was thought short very high rates would have greater efficacy, but the life-extension of those original tests have been difficult to reproduce. In short, it’s clear that continuous IVC by itself utilizes a powerful different anti-cancer mechanism to oxidative damage, but on it’s own it is not enough … perhaps because cancer was kept alive by the OXPHOS pathway. There are some other things as well that I think we need to look at also that the Nebraska study didn’t get quite right, including adding an OXPHOS inhibitor, and some other potentiators (oral Alpha Lipoic Acid, and some others) we would have seen at a minimum disease stabilization and reversal for most all 24 patients.

  3. lullabyman, yes this judicious avoiding of an optimal response was most strongly noticeable to me with the methylglyoxal, vitamin C, creatine combination. 400 mg of vitamin C ( as you noted in the form of Chewables?)??? Is that a joke? 400 mg of vitamin C might give you a pro-oxidant effect!!! I have a very difficult time figuring out why they would go for what is almost the minimum possible vitamin C dose. I am not totally sure what the state of the art of maximal vitamin C iv dosing might be, yet 200 grams might not be far off! We have reached an era of cancer research where there is an apparent lack of effort to gain every last inch of treatment power. Back in the 1970s there were human clinical trials in which a substantial percentage of the cancer patients had fatal side effects and the trial would continue without stoppage! In the current era there is often a large dose buffer in order to avoid toxicity of any kind. Avoiding any and all potential for the possibility of even temporary mild side effects is not consistent with the best interests of desperately ill cancer patients nor is it consistent with international human rights legislation.

    Yes, vitamin C + doxycycline was an impressive result. Hmm, vitamin C is a not so good an OXPHOS inhibitor? That sounds right, though of course references are wanted and needed! In terms of buying methylglyoxal without prescription, does this include chemically refined MG or only the refined Manuka honey?

    I remember seeing the Puerto Rican vitamin C study. It was just that I am always worried that something unexpected might happen when a treatment is changed around. As it is there is vitamin C, MG, and 3-BP which all have strong monotherapy selectivities for glycolysis and/or OXPHOS. Putting them together in an optimized treatment could give very impressive results.

    One might simply start with the basic treatments, acquire a comfort level with them and then up dose and reformulate.

    Perhaps a treatment could be something like:
    -Start with the generic MG protocol: 40 mg/kg/day oral MG taken in 4 divided doses, 500 mg oral vitamin C chewables, creatine etc.
    – With the generic protocol up dose the vitamin C and switch to iv dosing.
    – Perhaps updose somewhat with the MG.
    Fortunately there is an MG scavenger, aminoguanidine, so you can also have the comfort of knowing that you can control the downdosing PMID: 26530987
    -Move to iv MG dosing. D’s dosing suggestion for iv MG was 10 mg/kg/day which I would guess would give you much higher blood levels of MG. Still this would be 500+ mg per day iv which seems like quite a bit. It shows me that there is a fair amount of wiggle room involved in the dosing.
    – As the comfort level increased one might consider moving to NanoMG. PMID: 25999714
    I realize that most people want to avoid the synthesis route, though the benefits available from this synth are notable.
    The method that was used involves no complex chemical lab procedures at all.

    The big problem that appears to eternally recur when people avoid the synth lab is that they will up dose on the raw chemical: this is typically a very poor strategy. In one of the figures I saw on MG, it was quite startling to see that once a high dose was reached, even doubling the dosage resulted in no further increase in concentration in the cancer cells. What you would be doing is simply increasing the toxicity for all the normal cells.

    With NanoMg, you can down dose by almost a 100 fold and still have better response (This was in the mouse research)!
    What I do not fully understand, and lullabyman did refer to this aspect of dosing, is that after they down dosed by 100 TIMES starting with an already safe medication (MG) they did not seem to try and updose off the bottom. They seemed to go with a goodish result and not a home run. It is quite astonishing how much of metabolic press you have by up dosing MG and vitamin C at the same time. Pushing both on OXPHOS and glycolysis at certain doses seems to give you an exponentially increased treatment effect. This should not be that surprising. Once both energy pathways are stressed, additional stress should be expected to have large effects. The great part of this is that both MG and vitamin C could be reasonably up dosed to their very substantially clear toxicity profiles. Of course, with 1 mM vitamin C it is nowhere near a threshold of toxicity concern.

    It was actually quite striking in a url that I posted recently about the MG research that when they went from 1 mM MG and 1 mM Ascorbic acid to 2 mM MG and 2 mM ascorbic acid the viable cells went from roughly 28% to 7%. But we know that 2 mM Ascorbic acid is safe! Current maximum dosing hits perhaps 50 mM! I would love to see the dosing curves for different concentrations of MG and vitamin C (ascorbic acid). Remember these are both understood to be highly safe treatments so there does not seem to be an obvious justification for not exploring these doses. Admittedly, strange things can happen and sometimes do, though all too often we see that desperate patients often not highly ill-advised risks when the feel that they have run out of options. Combining a SPECIFIC OXPHOS inhibitor of cancer cells with a SPECIFIC glycolysis inhibitor of cancer cells seem a wiser choice. You have removed both sources of energy supply to cancer cells.

    There is just so much horsepower still under the hood with this it is quite amazing. As noted, we also have a Nobel prize winner on board for scientific cred. The patent that D cites above adds in yet more treatment power. They talk about using GSH depletors in nanoformulations etc.. This MG-vitamin C etc combo certainly looks better than I had realized.

    From this base, there are a range of other combos that you cycled through to mix things up. For example, as lullabyman suggested doxycycline, other energy depletors etc.. I am definitively getting a better feeling for an MG-centric treatment universe.

  4. lullabyman, I have begun to wonder: How much of the alternative medicine for cancer that is dismissed by mainstream medicine is in fact effective?

    Admittedly, my original impression of vitamin C was that it would be completely ineffective. Yet, after carefully considering the evidence I no longer believe such a stance is valid. From what I now understand, the entire 50 year argument about the effectiveness about vitamin C was completely bogus. The original results from Scotland should have immediately stopped all debate negating benefits to cancer patients.

    You mentioned IPT. This has also been widely dismissed by mainstream medicine. I do not have the same level of confidence in IPT as I do with vitamin C, though the ongoing blanket condemnation of alternative medicine certainly has started to raise flags for me.
    When people make categorical statements that then are proven false their credibility is very severely reduced. The questions about the effectiveness of 3-BP also fall in this category for me. How can you question the effectiveness of something such as 3-BP when the published patients showed nearly spontaneous responses which were simply enormous while not producing side effects. Recently I tried a cancer treatment called Cansema for a mole that I noticed was growing. Same thing! The FDA that chased the company out of the US, a lawsuit charging the product caused serious injury to a patient etc. . I read the testimonials was intrigued, bought the product and within a day or so the growth fell off! How do you maintain credibility when people can rapidly, easily and cheaply prove to themselves that the claims denying efficacy are false?

    I have started to wonder whether perhaps most well-established alternative treatments are at some level effective. This is likely untrue, though when everything alternative is condemned one is unable to differentiate treatments that might be effective and those that clearly are out there.

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