A List of Mitochondria Inhibitors, Disrupting Cancer Cell Function

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. Nevertheless, here is a nice explanation from a small biotech company, Immunomet (developing a Metformin-like drug IM156), on the importance of mithocondria inhibitors:

In many types of tumors, drug-resistant cells arising after treatment with a targeted therapy or chemotherapy drug show a metabolic profile that is distinct from the susceptible cells. Rapidly growing tumor cells that are sensitive to current therapies typically show enhanced activity of glucose uptake and glycolytic degradation of glucose to lactate to support their energy and biosynthetic needs. In contrast, the resistant subpopulations arising from many therapeutic treatments are slow growers that are highly dependent on mitochondrial metabolic activities – Krebs cycle and oxidative phosphorylation (OXPHOS) – for their biosynthetic and bioenergetic needs. These resistant cells harbor a greater ability to metastasize and initiate tumors, and therefore, eradicating the resistant subpopulations is a crucial aspect of modern anti-cancer drug development. The resistant population’s dependence on mitochondrial metabolic activities makes it highly susceptible to the metabolic regulators targeting OXPHOS, and the combination of OXPHOS regulators has been proven to be an effective treatment option in suppressing the recurrence of tumors in a wide variety of preclinical studies.” (Ref.)

One other example of a mitochondria inhibitor currently developed by Rafael Pharmaceuticals is is CPI-613 (Ref.1, Ref.2). 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. In contrast to that, when given prior to chemo they may lead to reduction of chemo effectiveness (I contacted Rafael Pharmaceuticals to check that but there was no response).

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, grouped depending on the mitochondria-related mechanism they disrupt (Figure 9 here is a nice Figure showing mitochondrial electron transport chain complexes involved in oxidative phosphorylation):

Mitochondrial complex I inhibitors:

  • Berberine (Ref.) – natural extract available as food supplement online
  • Papaverine (Ref.1, Ref.2) – inhibitor of mitochondrial complex I – FDA approved drug used primarily in the treatment of visceral spasm and vasospasm, and occasionally in the treatment of erectile dysfunction
  • Metformin (Ref.) – inhibitor of mitochondrial complex I – FDA approved drug – cheap and available
  • Pyrvinium Pamoate, – inhibitor of mitochondrial complex I (Ref.) – FDA approved drug – cheap and available but low absorption in the human body
  • Canagliflozin (Ref.) – FDA approved drug – cheap and available
  • Honokiol (Ref.). –  a natural substance – available as supplement online – inhibits complex I (Ref.)
  • NiclosamideNitazoxanideClosantel (Ref.) – FDA approved drug inhibiting complex I (Ref.)
  • Arctigenin (Ref.) – found in Arctium lappa, commonly called greater burdock – also an ingredient in Essiac tea for the alternative treatment of some cancers (Ref.) – inhibits complex I
  • Luseogliflozin (Ref.) – approved drug in Japan for the treatment of patients with type 2 diabetes mellitus (T2DM) (Ref.)

Mitochondrial complex II inhibitors:

  • Lonidamine – Inhibition of Mitochondrial Complex II but not easily available (Ref.)

Mitochondrial complex III inhibitors:

  • Atovaquone (Ref.), – FDA approved drug – cheap and available disrupting mitho complex III (Ref.)
    • It may even be a better option compared to Metformin as it reaches the blood plasma level required for its effectiveness. See. Ref.1 Ref.2 Ref.3

Mitochondrial complex IV inhibitors:

  • Tetrathiomolybdate (Ref.) – drug discussed previously on this website (Ref.)

Mitochondrial complex V inhibitors:

  • Meclizine, – Inhibition of Mitochondrial Complex V (Ref.1, Ref.2) – FDA approved drug – cheap and available
  • Bedaquiline – FDA-approved antibiotic inhibits mitochondrial ATP-synthase (complex V) (Ref.1, Ref.2)
  • Oligomicin (Ref.). – not approved – expensive, not safe and not easy to access – inhibits mitochondrial ATP-synthase (complex V) (Ref.)

Multiple complexes inhibitors:

  • Fenofibrate (Ref.) – and FDA approved drug inhibits Complexes I, II+III, and V (Ref.)
  • Troglitazone (Ref.) – FDA approved drug – cheap and available inhibits Complexes II+III, IV, and V –  most potently inhibits complex IV (Ref.)
  • Perhexiline (Ref.1, Ref.2) – approved for use as an anti-angina agent in Asia, Australia and New Zealand – inhibits complexes I and II (Ref.) as well as mitochondrial beta-oxidation of fatty acids (Ref.)

Other mitochondria inhibiting mechanism:

  • Artemisinin – disruption of mitochondria function (Ref.1, Ref.2) – plant extract previously discussed on this website (Ref.)
  • Doxycycline, – FDA approved drug – cheap and available – inhibits Mito Biogenesis – inhibits mitochondrial protein translation (Ref.)
  • Tigecycline (Ref.) – FDA approved drug – injectable – inhibits Mito Biogenesis – inhibits mitochondrial protein translation (Ref.)
  • Azithromycin – FDA approved drug – inhibits Mito Biogenesis – inhibits mitochondrial protein translation (Ref.)
  • Salinomycin (Ref.) – not approved – expensive, intravenous, already used on humans and shown to be effective against cancer – rapid hyperpolarization of mitochondria and mitochondrial matrix acidification

The exact mechanism unknown (at least to me):

  • Propranolol (Ref.1, Ref.2, Ref.3) – FDA approved drug – oral, cheap and available
  • Caffeic acid phenyl ester (CAPE) from propolis (Ref.)


  • Perphenazine and trifluoperazine (Ref.)
  • MethylGlyoxal (Ref)
  • Limonin – a natural extract (Ref.)
  • Here is an article including additional mitho inhibitors (Ref.) and here is another one (Ref.)
  • Bullatacin and other Acetogenins from Graviola (Ref.0, Ref.1, Ref.2)
  • Large list of mitochondria inhibitors (Ref.)

Here is a list of Natural Products Targeting the Mitochondria in Cancers:

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


  • 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).
  • interestingly, it has been suggested that mito inhibitors such as Metformin combined with proton ionophores such as Salinomycin, would induce a “Warburg trap” in tumor cells where they initially switch to glycolisis due to the mito inhibitors . However, glycolisis would than lead to increased acidity around the tumors.  Salinomycin on the other hand, due to its proton inophore action, will get the protons back into the tumors, which is not what cancer cells like. So they will try to push protons again out of the cells consuming all the energy. If the cell tries to produce more energy will only be able to do that via glycolisis which again leads to the production of protons. This is what is called “Warburg trap” and this is the point when cancer cells have to slow down and eventually die due to a high intracellular acidity. Please read this paper for more details (Ref.). In the same paper, the authors state the following: “We therefore suggest that post-surgery treatment with MCI inhibitors alone or as the Warburg trap drug combinations could be considered as a supportive therapy component, especially in cases of patients with tumors scored high for Wnt signaling, to prevent their tumor recurrence risk.” I think this is a nice idea for a treatment strategy where I would combine two mito inhibitors (Metformin and Doxycicline) and Salinomycin as a proton inophor.
  • However, there is an unknown aspect regarding the combo of 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), which is why Canaglifozin is today used as an anti diabetic drug –> inhibition of some (but not all) glucose transporters (Ref.). And the open question is if is is good to combine the two:
    • a drawback could be that Canaglifozin  may reduce the 2DG absorption in the cancer cells.
    • the advantage on the other hand could be that Canaglifozin will reduce not only 2DG absorption in the cancer cells but also that of glucose – this in turn may even lead to higher anti cancer effects but also possibly higher side effects as normal cells will also be affected by these two drugs

Update July 8th, 2019: A paper recently published in Nature suggests that inhibition of BACH1 by an FDA approved drug Heme (marketed as Panhematin) makes cancer cells more dependent on mitochondrial respiration and as a result more susceptible to mitochondria inhibitors (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.

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.

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).

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.

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[0]=3174&path[1]=6141

Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

Use of tigecycline for treatment of cancer https://patents.google.com/patent/WO2011109899A1/en

Cancer stem cells exhibit different metabolic profiles from other cancer cells, such that they do not readily respond to treatment using conventional chemotherapeutic agents. Studies disclosed herein now demonstrate that the glycylcycline antibiotic tigecycline (a tetracycline derivative) exhibits anti-cancer activity, including activity against cancer stem cells. This anti-neoplastic activity appears to be due to inhibition of mitochondrial protein synthesis in the cancer cells. In preferred embodiments, the cancer to be treated is a hematological cancer, such as leukemia, lymphoma or myeloma.

Oxidative Phosphorylation as an Emerging Target in Cancer Therapy https://www.ncbi.nlm.nih.gov/pubmed/29420223

Cancer cells have upregulated glycolysis compared with normal cells, which has led many to the assumption that oxidative phosphorylation (OXPHOS) is downregulated in all cancers. However, recent studies have shown that OXPHOS can be also upregulated in certain cancers, including leukemias, lymphomas, pancreatic ductal adenocarcinoma, high OXPHOS subtype melanoma, and endometrial carcinoma, and that this can occur even in the face of active glycolysis. OXPHOS inhibitors could therefore be used to target cancer subtypes in which OXPHOS is upregulated and to alleviate therapeutically adverse tumor hypoxia. Several drugs including metformin, atovaquone, and arsenic trioxide are used clinically for non-oncologic indications, but emerging data demonstrate their potential use as OXPHOS inhibitors. We highlight novel applications of OXPHOS inhibitors with a suitable therapeutic index to target cancer cell metabolism.

3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions https://www.sciencedirect.com/science/article/pii/S0014482714000263

NADH autofluorescence, a new metabolic biomarker for cancer stem cells: Identification of Vitamin C and CAPE as natural products targeting “stemness” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400535/

Here, we assembled a broad molecular “tool-kit” to interrogate the role of metabolic heterogeneity in the propagation of cancer stem-like cells (CSCs). First, we subjected MCF7 cells to “metabolic fractionation” by flow cytometry, using fluorescent mitochondrial probes to detect PCG1α activity, as well ROS and hydrogen-peroxide (H2O2) production; NADH levels were also monitored by auto-fluorescence. Then, the various cell populations were functionally assessed for “stem cell activity”, using the mammosphere assay (3D-spheroids). Our results indicate that a sub-population of MCF7 cells, with increased PGC1α activity, high mitochondrial ROS/H2O2 production and high NADH levels, all form mammospheres with a higher efficiency. Thus, it appears that mitochondrial oxidative stress and the anti-oxidant response both contribute to the promotion of mitochondrial biogenesis and oxidative metabolism in CSCs. Further validation was provided by using specific inhibitors to target metabolic processes (the NAD+ salvage pathway, glycolysis, mitochondrial protein synthesis and OXPHOS), significantly reducing CSC propagation. As a consequence, we have now identified a variety of clinically-approved drugs (stiripentol), natural products (caffeic acid phenyl ester (CAPE), ascorbic acid, silibinin) and experimental pharmaceuticals (actinonin, FK866, 2-DG), that can be used to effectively inhibit CSC activity. We discuss the use of CAPE (derived from honey-bee propolis) and Vitamin C, as potential natural therapeutic modalities. In this context, Vitamin C was ∼10 times more potent than 2-DG for the targeting of CSCs. Similarly, stiripentol was between 50 to 100 times more potent than 2-DG.

Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer https://www.mdpi.com/1422-0067/20/1/229/htm

Ovarian cancer is the leading cause of death from gynecologic malignancy in the Western world. This is due, in part, to the fact that despite standard treatment of surgery and platinum/paclitaxel most patients recur with ultimately chemoresistant disease. Ovarian cancer is a unique form of solid tumor that develops, metastasizes and recurs in the same space, the abdominal cavity, which becomes a unique microenvironment characterized by ascites, hypoxia and low glucose levels. It is under these conditions that cancer cells adapt and switch to mitochondrial respiration, which becomes crucial to their survival, and therefore an ideal metabolic target for chemoresistant ovarian cancer. Importantly, independent of microenvironmental factors, mitochondria spatial redistribution has been associated to both tumor metastasis and chemoresistance in ovarian cancer while specific sets of genetic mutations have been shown to cause aberrant dependence on mitochondrial pathways in the most aggressive ovarian cancer subtypes. In this review we summarize on targeting mitochondria for treatment of chemoresistant ovarian cancer and current state of understanding of the role of mitochondria respiration in ovarian cancer. We feel this is an important and timely topic given that ovarian cancer remains the deadliest of the gynecological diseases, and that the mitochondrial pathway has recently emerged as critical in sustaining solid tumor progression.

Hallmarks of cancer stem cell metabolism https://www.nature.com/articles/bjc2016152

Cancer cells adapt cellular metabolism to cope with their high proliferation rate. Instead of primarily using oxidative phosphorylation (OXPHOS), cancer cells use less efficient glycolysis for the production of ATP and building blocks (Warburg effect). However, tumours are not uniform, but rather functionally heterogeneous and harbour a subset of cancer cells with stemness features. Such cancer cells have the ability to repopulate the entire tumour and thus have been termed cancer stem cells (CSCs) or tumour-initiating cells (TICs). As opposed to differentiated bulk tumour cells relying on glycolysis, CSCs show a distinct metabolic phenotype that, depending on the cancer type, can be highly glycolytic or OXPHOS dependent. In either case, mitochondrial function is critical and takes centre stage in CSC functionality. Remaining controversies in this young and emerging research field may be related to CSC isolation techniques and/or the use of less suitable model systems. Still, the apparent dependence of CSCs on mitochondrial function, regardless of their primary metabolic phenotype, represents a previously unrecognised Achilles heel amendable for therapeutic intervention. Elimination of highly chemoresistant CSCs as the root of many cancers via inhibition of mitochondrial function bears the potential to prevent relapse from disease and thus improve patients’ long-term outcome.


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77 thoughts on “A List of Mitochondria Inhibitors, Disrupting Cancer Cell Function

  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.

        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.

      1. Sorry, D, don’t want to overwork you, though Salinomycin should be up there as well.

        Your list of mitochondrial inhibitors is super important because in combination with glycolysis inhibitors there can be powerful treatment effects. Take away of OXPHOS take away glycolysis what’s left?

        With the list in hand you have a good starting point to seeing what the research has to say. What is somewhat surprising is that the url below is only now reporting the combination of DCA with Salinomycin. The list above would help you stay abreast or even ahead of the research.

        1. J, no overwork. Thanks a lot and please continue help improve the content! I added Sal as well. Indeed it is a very important one that I very much like due to effectiveness. Also nice to see the recent paper on Sal and DCA https://www.nature.com/articles/s41598-018-35815-4#ref-CR16 It’s interesting to see that DCA is such a good MDR inhibitor. If you remember, Emad succeeded to improve the response of his mom to chemo by adding DCA prior to Taxol, which is also suggested by some scientific papers.

  5. I have been looking at https://www.ncbi.nlm.nih.gov/pubmed/?term=30428319
    Very impressive! They have created a mito version of Honokiol that is 100 times more potent than the unformulated verions , with apparently a large amount of room to dose up. The synthesis is presented on page 13 of https://ars.els-cdn.com/content/image/1-s2.0-S2589004218300452-mmc1.pdf Perhaps this version should be added to the writeup above for Honokiol.

    It is truly astonishing! We are moving to a point where there are very very powerful anti-cancer products.

    Mito-CP was also found to be an OXPHOS depletor.
    Synergized with 2-DG in a mouse model of breast cancer.

    What is especially startling from the below url is that they also used Mito-Q with 2-DG and it also synergized.
    But Mito-Q is a commercially available supplement over the counter!
    I am not sure what dosing would be needed for the anti-cancer effect, though I had no idea that Mito-Q could be used in this way.
    It was not clear to me how an antioxidant such as Mito-Q could be turned into an oxidant, though one of the articles suggested that this is analogous to how vitamin C also transforms from an anti- to a pro oxidant.


  6. D, here’s another glycolysis inhibitor, limonin, from oranges etc.

    “In present study, we demonstrated that limonin had a profound antitumor activity against HCC cells by suppressing tumor glycolysis and inducing cell apoptosis.”

    This is so great! We have an ever expanding list of glycolysis and mitochondrial inhibitors! As the authors note limonin is a natural product and thus likely reasonably safe. Combining a glycolsyis and mitochondrial inhibitor could have very powerful anti-cancer effects, all the more so if given metronomically. I will be very interested in seeing how the research unfolds using these combinations.


  7. Thank you D for updating the list!
    I continue to more fully appreciate the importance of combo glycolytic/mito inhibition.

    I am not totally sure about limonin being a mitochondrial inhibitor; it seems more of a glycolytic inhibitor.
    Let’s have a glycolytic inhibitor page!

    I have been reading up on LDH inhibitors. It has always been a great mystery as to why there has not been more of a push to move these through the regulatory system. There are people who have loss of function mutations in LDH-A and live with few if any side effects. This is of central importance to cancer because if cancer cells were to lose LDH function they likely would not remain viable. A few years ago it was discovered that stiropentol is an LDH-A inhibitor.


    1. D, you noted that stiripentol is FDA approved. However, I had not fully tuned into that.
      Stiripentol was FDA approved as of August 20, 2018.


      This could be of considerable importance in the treatment of cancer.
      One might wonder how effective for example, treating with methylglyoxal ({even better NanoMG}, which would push up glycolysis selectively in cancer cells) followed up with stiripentol might be. Such a combination would accelerate glycolysis while at the same time shutting down the only remaining pathway to fully metabolize the glucose and recycle the NADH.

      Stiripentol interacts with almost everything so it would best done cleanly (i.e., without all sorts of complex combinations), though this does appear to be quite promising. LDH is possibly the most conspicuous element of cancer’s metabolism that has not been
      addressed up till this point.

  8. D, tocotrienol is a surprisingly effective glycolytic inhibitor!

    Figure 3 shows that 8 micromol gamma-Tocotrienol reduces MCT-1 levels to very close to zero. In fact many other glycolytic enzymes such as HK-II, PKMA, and LDHA also went to near zero at 8 micromol.

    Figure 2 of https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703733/ shows that in human dosing studies
    10 micromol Cmax is achievable with 1600 mg. Table 2 found no side effects of this dose levels in a clinical trial.
    Combining highish dose tocotrienol with a mitochodnrial inhibitor such as methylglyoxal etc. might be a very powerful
    treatment. This would be all the more true in nanoformulations.

    1. One more added:
      Arctigenin (Ref.) – found in Arctium lappa, commonly called greater burdock – also an ingredient in Essiac tea for the alternative treatment of some cancers (Ref.)

    2. Hey J, look what I found … this is extremely interesting:

      As we know, finding powerful and available glycolisis inhibitors that do not work only in the lab but in humans as well is not easy. Furthermore, finding LDH inhibitors that are both available and effective is even more challenging. Yet, it seems we now have one. That is called Stiripentol http://science.sciencemag.org/content/347/6228/1362 It’s a LDH1 and LDH5 and seems to be 50 to 100 times more potent than 2-DG in killing cancer stem cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400535/

      Stiripentol is an FDA approved drug https://en.wikipedia.org/wiki/Stiripentol

      Together with Ketogenic diet seems to be effective in addressing epilepsy https://www.jns-journal.com/article/S0022-510X(16)30804-8/fulltext

      According to the paper published in Science and cited above Isosafrole seems to be an even more potent inhibitor of LDH but because it can be converted in ecstasy, it may be difficult to buy.

  9. D, this is great! Thank you!

    There are a few different takes on mitochondrial approaches to cancer.
    For example, https://www.ncbi.nlm.nih.gov/pubmed/?term=23690779 found that mitochondrial stimulation with forskolin and mito complex 1 inhibition “strongly increases their sensitivity”

    Another perspective on mitonchondria relates to the fission / fusion state.
    Cancer cells are fission dominant. Yet, there are nutritional approaches to changing the fission fusion balance.

    Interestingly, imbalance of the mitochondria phenotype toward fragmentation orchestrates the migratory capability in cells where migration represents a crucial physiological function, such as T-cell lymphocytes and tumoral metastatic cells[30,31]. Indeed, in order to make movement possible, mitochondria need to be fragmented to favor their relocalization and recruitment to specific subcellular regions. In the case of tumoral cells, a direct correlation has been demonstrated between the metastatic degree and the Drp1-dependent fragmentation of mitochondria in breast cancer[31]. Mitochondrial fission requires the cytosolic dynamin related protein 1 (Drp1) and its mitochondrial receptors fission 1 (Fis1), mitochondrial fission factor (Mff) and Mitochondrial Division (Mid) 49 and 51. Conversely, the outer membrane mitofusin (Mfn) 1 and 2 and the inner membrane dynamin-like protein optic atrophy 1 (Opa1), mediate mitochondrial fusion[32,33].


    Here is some of the discussion from the below forum on how to manipulate fission/fusion/biogenesis
    Supplement for fusion: C18:0 — stearic acid

    “Day 3 and 4 FUSION: 5 -10gm Stearic Acid + 20mg PQQ 1 hour later + 2 capsules BroccoMax
    This was 1g of Vitacost brand, taken with 10g stearic acid, 400mg ALA, and 20mg PQQ.

    When you eat stearic acid in the form of a piece, then part of stearic acid is not absorbed by the body.

    To increase the efficiency of absorption, you need a surfactant. This is necessary so that a significant part of stearic acid is transferred to chylomicrons.

    Soy lecithin is a surfactant. It allows better emulsification of stearic acid in the intestine.

    If you melt lecithin with stearic acid and mix very thoroughly, the degree of absorption may increase by 10 times (and even more). Moreover, the degree of discomfort can be greatly reduced if you have it.

    Day 4: Fusion/biogenesis
    Stearic acid (fusion) — 5-10 g
    Leucine (biogenesis) — 5g
    PQQ (biogenesis) — 20mg
    Hydroxytyrosol (biogenesis & antioxidant) — 25mg
    Vitamin B complex (commercial mix)

    Leucine — 5g
    PQQ — 20mg
    Hydroxytyrosol — 25mg

    Day 5: Fusion/biogenesis
    Morning & evening
    Leucine — 5g
    PQQ — 20mg
    Hydroxytyrosol — 25mg

    1. :))) this is very funny … I actually did not had the chance to check it when you added the reference, and now I was doing some research for a paper I need to work on and I came across this one … very nice coincidence, and it was under my nose, so you were the first to find it: Congratulations for that! 🙂 I really think this is a very important tool we now have.
      In my view, it’s at the same level of importance as is Metformin for targeting mitochondria.

  10. D, yes you are so right.
    Having a button to push down LDH-A levels is substantially important.
    I do not know why this had not been a greater priority for the pharmaceutical companies.
    It is such an important metabolic target!

    If you can shut off lactate metabolism, then cancer cells would not be able to regenerate NAD/NADH.
    They would not be able to export LDH to acidify their surroundings.
    Lots of nice things start to happen.
    It might even be better than simply shutting off glycolysis.
    With LDH inhibition, what you might want to do is upregulate glycolysis!
    Cancer cells would then be furiously uptaking glucose, but it would not be expelled as lactate.

    There are people who have loss of function mutations in LDH-A and there are no great side effects.
    I am just somewhat unsure about how safe stiropentol might be.

    Tocotrienol also has large anti-LDHA action.

    1. Hi J, at this point I would give the best score to Stiripentol in terms of LDH inhibition. Safety profile is well know. I think the question is how strong the side effects are. But clearly considerably lower vs chemo.
      Thanks again for your contribution J.
      I added above, as a mito inhibitor, CAPE from propolis – this is still a subject I would like to address with a specific post focused on propolis.

  11. D, this is great!!!
    We are starting to hit some real traction with these metabolic inhibitors!
    Anyone else out there who wants to chime in, please do!

    The whole idea here is that each of these inhibitiors have different properties.
    If you could take a nice safe glycolysis inhibitor, and then try different respiration inhibitors such as methylglyoxal,
    then you might hit something that really clicked.

    One of the big problems that I have seen in the past is that at a certain point people simply run out of ideas.
    They no longer have any clue left of how to fight it.
    With all these inhibitors and all these combinations and variations in dosing and scheduling, people would never
    be left without something else to try.

    D, a while back you were saying that everything connects back.This is so so true!
    I have been looking into toothpaste with theobromine (It actually contains no bromine. The derivation is theo -god , broma food, thus food of the gods). Theobromine greatly increases the hardness of hydroxyapetite which is what teeth are made of.
    Harder teeth = less cavities.

    Theobromine is what gives chocolate its chocolatiness.
    It is also quite dangerous to many animals especially dogs.
    It turns out that theobromine is almost chemically identical to caffeine and it is also a respiration inhibitor.


    1. J, very interesting.
      It’s nice to see how everything connects. Now we even have Essiac team on our list above.
      These days I was doing some deep research and also came across DMSO as a MTC inhibitor. That is very interesting.
      Yes, there are many options. I can imagine that our discussion has become a little hardcore for some readers, so at some point next years I would like to translate this into more easier to understand strategies.

  12. A present for those on the forum:

    Alternative sugars and in particular mannoheptulose (also 2-DG) certainly have potential as cancer therapeutics. Note however, that the dosage calculations give from the article reproduced below do not appear correct. 1.7 mg/g in mice is not equivalent to 119 g for a 70 kg person. I believe the correct dose would be closer to 9g.

    “These sugar analogs do look interesting. However, notice what appears to be a mistake in the above article–
    Rates of growth of human tumors in experimental animals are dramatically reduced (by 65-79%) by a dose of 1.7 mg/g mannoheptulose daily for 5 days.”

    Mannoheptulose is a naturally occurring sugar, its usual route of purification being from avocados (Persea gratissima), and is anticipated to be of low toxicity. These aspects make it suitable for consideration as a potential therapeutic agent. However, the I50 of GK for mannoheptulose is relatively high at about 12.5 mM. This implies that, were this sugar considered as a potential
    treatment, high doses would be required. Equivalents of the daily doses given to experimental animals during the present study would be 1.7 g/kg for human patients (119 g for an average-sized person of 70 kg). This is a high dose, and no information is available concerning a minimum effective dose. On the positive side, the sugar is very soluble and stable, and administration in the form of a drink might be possible.

    Few toxic side-effects are anticipated from mannoheptulose administration. Previous studies failed to uncover toxicity towards
    experimental animals beyond reversible suppression of insulin secretion and transient hyperglycemia.”

      1. D, this is the first that I have ever heard of glucokinase being a near tumor specific enzyme.

        My understanding had been that glucokinase was HK4 and it was active in the liver and that was about it. This seems important. It is another notable way in which cancer cells are quite different from normal cells. If this result had held up through time I am not sure why the standard tumor cell glycolysis figures do not make not of this significant detail. From the article it would appear that GK is active in a quite wide range of tumor types. A nanoformulation might also be helpful.

  13. At least as a theoretical presentation I have liked this article for quite some time,

    Yet, I have not been sure how one might attempt to perform such a treatment in the real world. The below article suggests that extreme metabolic therapy might indeed be possible. As noted in the article a variant of the protocol has already been tried in humans and has ethical approval.

    1. Hi J, Thanks for the article above (30037608). This is very interesting. When I have time I will get in contact with the authors. This approach may work very well when combined with conventional treatments which could be used in low dose. I like the idea of using Somatostatin (to suppress glucagon secretion) and a combination of both α and β-blockers (specifically the adrenergic antagonists, Phentolamine and Propranolol), to block epinephrine and norepinephrine actions. Specifically, reduction of cerebral glucose demand by Propranolol is also relevant during 2DG treatments.

  14. Good One D!

    Sometimes I have encountered treatments such as CAPE, or TRAIL before and I thought that they were totally inaccessible to patients. I did not realize that CAPE was a natural product very roughly equal to honey!

    Having this list of OXPHOS inhibitors and another list for glycolysis inhibitors could be of enormous help. People could simply load up on them and start combining. Each of them have their own unique profile so working through different combinations might result in one that directly hit the mark. I find it encouraging how effectively CAPE shut down OXPHOS and then pushed up glycolysis. The one two punch of reducing OXPHOS and then reducing glycolysis certainly has appeal.

  15. D when you have a spare moment might you add a stub for a list for glycolytic inhibitors?
    I am interested in consolidating our knowledge into lists and then perhaps a master list.
    Having all the site information on one spread sheet would be a great way of keeping track of things.
    I think it would have been much easier to spot the importance of FB if it had been part of a master list.

    1. johan, thank you for that suggestion! Perhaps we could get D interested in porting that software to this blog.

      In biology and especially in cancer, there are so many of these intricate wiring diagrams that have a lot of information that is often difficult to organize. Something like coggle could help us! It would be great if we could have the various pathways (glycolysis, OXPHOS, etc) all on one map with all of the different possible treatments in one central place. I have tried putting them into a paint file though they all sooner or later get swished together.

  16. yes, exactly what I had in mind! I know Daniel’s extremely busy now but I hope this can be implemented as it would really add value, and it’s easy to update and collaborate.

    1. @marcos: Atovaquone is a component of the anti-malarial Malarone, which can be bought from many online pharmacies. But if you tell them the truth (you want to use it as anti-cancer), they probably won’t sell it to you, unless you have a prescription. A workaround could be to tell them you are going to travel to a country, where Malarone is effective (but I don’t know which country to choose) in preventing malaria infection. However, I have some doubts about Atovaquone, regarding tissue distribution, which may be sub-optimal.

      1. Not very scientific, but the wiki says so. 🙁


        “Acetogenins from Annonaceae are even more potent inhibitors of complex I. They cross-link to the ND2 subunit, which suggests that ND2 is essential for quinone-binding.[36] Rolliniastatin-2, an acetogenin, is the first complex I inhibitor found that does not share the same binding site as rotenone.[37]”

        “The antidiabetic drug Metformin has been shown to induce a mild and transient inhibition of the mitochondrial respiratory chain complex I, and this inhibition appears to play a key role in its mechanism of action.[40]”

  17. Just catching up. Thanks for much for all of this. It is so very hard to navigate all of the different pathways, attacking it from so many sides.

    1. Thank you J. very interesting.

      Its found in common wormwort ( Dioscorea communis , syn .: Tamus communis L. ) https://de.wikipedia.org/wiki/Gemeine_Schmerwurz

      “Because of the saponins and calcium oxalate contained in the plant parts, the orchid is poisonous. Rubbing the juice of the berries or the roots on the skin can cause skin irritation caused by tiny oxalate crystals and histamine in the juice. [5] The root further includes phenanthrene derivatives and glycosides dioscin and gracillin as well as their derivatives. In a laboratory study, there was evidence of anti-inflammatory effects of the root sap. [6] In folk medicine, inter alia, the plant was previously against rheumatismand bruises, hence the French name “herbe aux femmes battues” (“herb of the beaten women”). Today it still plays a role in homeopathy .”

      Kind regards,

  18. I am new here so apologies if this is in the wrong place.

    This topic looks a little scary to me. 8 years ago my cancerous ovary ruptured and I was diagnosed in surgery with stage 3 endometrial adenocarcinoma – I was in the best shape of my life doing everything right, and too young and thin for this cancer.

    My ND convinced me to do carboplatin/paclitaxel and he gave me IVC and artesunate, high dose melatonin, mushrooms, and nutrients with glutathione. I beat the cancer but descended into the hell of ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome.

    Turns out, I had undiagnosed hemochromatosis, appearing gradually after my hysterectomy. I believe the excess iron combined with the artesunate and C and not only killed the cancer cells, but damaged my mitochondria, leading to my immune system being damaged, and reactivated HHV6, cytomegalovirus, EBV as well as chronic chlamydia and mycoplasma pneumoniae, which triggered multiple autoimmune conditions. I was sleeping 16 hours a day, had trouble exercising and couldn’t think or read.

    Nothing natural worked to help this mess – it took hydrocortisone, intravenous immunoglobulins (which I still am on), 3 years of valganciclovir, 4 months of IV azithromycin, rifampin, and doxycycline to begin to improve. But I was still fatigued.

    So, 4 years ago, I embarked on the mito correction strategy from the paper Seyfried, D’Agostino, and Nicolson wrote, a year before it came out. Rebuilding my membranes with phospholipids, cleaning them out with PolyMVA and ALA, and using antioxidants and B vitamins and branched chain amino acids has greatly helped, however I still cannot tolerate aerobic exercise, though I am able to slowly exercise which I’ve done as much as I can and I now sleep 7 hours a day.

    Testing has shown impaired complex I, hyperactive complex IV (400% of normal). Metabolic treadmill testing showed abnormal results – I do almost all glycolysis, even laying still on a table, and only did FAO when I initially got on the treadmill before switching back to glycolysis.

    Nervous about my wonky immune system, I recently had testing showing circulating cancer stem cells. Nothing has been found in imaging but I haven’t had a PET. My oncologist, at 5 years, said he was surprised I hadn’t had a recurrence with how bad it was when he met me. I’m looking for what to do and a FB group recommended your site.

    I read through all of the above. Have I been doing the wrong thing trying to fix my limping mitochondria? Would the treatments above, done of which damaged me in the first place help me or would they send me back to the hell I was in 6 years ago? Is damaging my mitochondria a good thing or could it render me bedbound for life? What about my immune system?

    I know you don’t have a crystal ball here, so I’m not expecting answers. But I am curious about any general thoughts you have about the dangers of impairing mitochondria and how one balanced the good with the bad.

    Thank you for the excellent work you’ve been doing and for making a place for intelligent conversation.

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