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
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).
- 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.).
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 Restriction. https://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.
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