Potential solutions against Cachexia: Glutaminolysis inhibitors and more

Conclusion

To avoid cachexia we need to reduce the request for glutamine via lactate (see the seven points below) and in order to kill cancer cells relying on glutamine we should reduce/inhibit glutaminolysis (e.g. EGCG), reduce glutamine transport (retinoic acid), reduce blood glutamine (phenylbutyrate and avoid (red) meet).

Background

Cachexia is loss of weight, muscle atrophy, etc.in someone who is not intendingto lose weight. This is sometimes seen in cancer patients.

Cachexia has its origin in the fact that one of the major fuels supporting the energy productionof cancer cells isGlutamine, the most abundant amino acid in the plasma. Indeed, next to Glucose, Glutamine is one of the main element through which mammalian cells fuel their growth and proliferation. Glutamine is metabolized throughmitochondrial glutaminolysis and converted in energy required for the activity of cancer cells. As a result of theglutamine need, body wide signaling mobilizes glutamine from host muscle hence the cachexia observed in the host. (Note that tumorsnot visible on PET scan are probably relying strongly on this process. The good aspect about these tumors is that they are not evolving fast.).

On this line, inhibiting mitochondria, inhibiting Glutaminolysis, inducing Glutamine deprivation (or even better a combination of all) should help inhibit Cachexia and if the cancer cells will not switch to other source of energy this will evenkill cancer. Obviously, combining this approach with Glucolysis inhibition (with e.g. 2DG) and/or Glucose deprivation (via e.g. diet) will lead to an even better cancer killing strategy.

–> Targeting Mitochondria

Since glutaminolysis is a mitochondrial dependent process, drugs targeting cellular mitochondria may be used for an effective anti-cancer treatment for those tumors strongly dependent on Glutamine:

Doxycycline:
Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.http://www.ncbi.nlm.nih.gov/pubmed/25625193
Note: this is acommon antibiotic taken typically at 200mg/day

Metformin:
Inhibition of Complex I in Citric Acid Cycle :Cancer cells that depend on glutamine cause the mitochondria to produce anabolic precursors using glutamine instead of glucose. Glutamine will flow in and out of the citric acid cycle and will cause NAD+ to be regenerated continuously using the electron transport chain. Drugs have been developed to suppress these effects in the mitochondria of cells, and Metformin is one of them.Metformin not only targets glutamine metabolism but also lowers blood glucose concentration. (Ref.)
“Metformin alone or together with 2-DG inhibited glutamine consumption” (Ref.)
However, other studiessuggest that metformin treatment increased the dependency of prostate cancer cells on reductive glutamine metabolism and that metformin combined with specific inhibitors of glutamine metabolism might be synergistically beneficial in prostate cancer treatment (Ref.)
Note: this is acommon anti diabetic drugtaken typically at 1000mg/day

HCA:
to inhibit citric acid cycle as well
Note: this is a supplementtaken typically at 1500mg/day

Phospoethanolamine & Meclizine

–> TargetingGlutaminolysis

Epigallocatechin gallate (EGCG):
a green tea polyphenol, has numerous pharmacological effects, one of which is to inhibit GDH (80). The effects of EGCG on GDH have been used to kill glutamine-addicted cancer cells during glucose deprivation or glycolytic inhibition (17, 18) and to suppress growth of neuroblastoma xenografts (15). http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754270/
Note: this is a supplementtaken typically at 3000mg/day

Cysteine
ASCT2 (SLC1A5) is the transporter responsible forbalancing the intracellular amino acid pool including Glutamine. Inhibition ofthis transporter will lead to reduced inracellular Glutamine which is desired if the cancer cells are relying on this amino acid to produce energy.Cysteine, seems to be an inhibitor of this transporter: “It was found that Cys is a potent competitive inhibitor of hASCT2 but is not a substrate. Moreover, Cys binding to a second site, different from that of substrate, triggers a protein-mediated unidirectional Gln efflux.”http://www.febsletters.org/article/S0014-5793(15)00935-7/abstract
Note: This is a supplements available online.Cysteine-providing substances like NAC (N-Acetyl Cysteine)are also available as supplements (but note that this is a strong antioxidant and thus not suitable with prooxidant cancer treatments such as 3BP)

Retinoic acid (Vitamin A)
Retinoic acid it is a known drug with serious anti cancer properties. It is actually used by Dr. Dana Flavin on many of her cancer patients. What is less known is itsASCT2 (SLC1A5) inhibition property. Here is a recent study indicating that Retinoic acid can indeed reduce ASCT2: Inhibition of ASCT2 is essential in all-trans retinoic acid-induced reduction of adipogenesis in 3T3-L1 cells http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511454/
As a funny note, this study also indicates that “Inhibition of Asct2 by daily vitamin A intake may be sufficient to reduce obesity.”
Note: this drug is available online without prescription but also widely available at pharmacies (in which case a prescription may be required depending on the country).

–> Glutaminedepletion

Phenylbutyrate:
Lowers blood glutamine
Note: this is a drugtreat urea cycle disorders takenat5 to 10 gram/day in cancer treatment; it is very expensive but with prescription it may covered by the insurance

–> Others

c-Myc inhibitors: In addition to its known function in regulating the cell cycle and glucose metabolism, recent studies indicatea role for Myc in stimulating glutamine catabolism (Ref). On this line, it has been suggested that inhibition of Myc is a good anti cancer strategy specificallythose tumors strongly dependent on Glutamine:

Butyrate:
butyrate was shown to reduce the expression of c-Myc mRNA and protein expression in leukemia, prostate and colon cancer cell lines during the course of cell differentiation [119-121]. Given the role of c-Myc in promoting glutaminolysis in cancer cells and inducing the expression of glycolytic enzymes, it is tempting to speculate that reduced c-Myc expression by butyrate treatment might contribute to normalization of cancer cell metabolism.https://www.dkfz.de/en/tox/download/gerh/pdf-files/Biomedical-Research-Clarissa-Gerhauser.pdf
Note: this is a supplementtaken typically at few grams/day

Apigenin, Diclofenac, Baicalein can also reduce c-MYC

Fish oil: Eicosapentaenoic acid (EPA, an omega-3 fatty acid from fish oils) for the treatment of cancer cachexia: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572135/#R104

–> Inhibiting intracellular lactate signaling 

Lactate promotes glutamine uptake and metabolism in oxidative cancer cells http://www.tandfonline.com/eprint/tsQqJkgZFP2nRfk7WqHP/full Oxygenated cancer cells have a high metabolic plasticity as they can use glucose, glutamine and lactate as main substrates to support their bioenergetic and biosynthetic activities. Metabolic optimization requires integration. While glycolysis and glutaminolysis can cooperate to support cellular proliferation, oxidative lactate metabolism opposes glycolysis in oxidative cancer cells engaged in a symbiotic relation with their hypoxic/glycolytic neighbors. However, little is known concerning the relationship between oxidative lactate metabolism and glutamine metabolism. Using SiHa and HeLa human cancer cells, this study reports that intracellular lactate signaling promotes glutamine uptake and metabolism in oxidative cancer cells. It depends on the uptake of extracellular lactate by monocarboxylate transporter 1 (MCT1). Lactate first stabilizes hypoxia-inducible factor-2α (HIF-2α), and HIF-2α then transactivates c-Myc in a pathway that mimics a response to hypoxia. Consequently, lactate-induced c-Myc activation triggers the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1), resulting in improved glutamine uptake and catabolism. Elucidation of this metabolic dependence could be of therapeutic interest. First, inhibitors of lactate uptake targeting MCT1 are currently entering clinical trials. They have the potential to indirectly repress glutaminolysis. Second, in oxidative cancer cells, resistance to glutaminolysis inhibition could arise from compensation by oxidative lactate metabolism and increased lactate signaling.

Next to the above, here is another recent paper supporting the fact that the more acidity is around the tumor the more the tumor will need glutamine so that it can continue growing:

A proposed role for glutamine in cancer cell growth through acid resistance http://jn.nutrition.org/content/131/9/2539S.full Cancer cells exhibit a greatly increased level of aerobic glycolysis with accumulation of lactic acid, a phenomenon known as the Warburg effect. Apparently, survival of cancer cells requires an elaborate system for acid resistance. L-glutamine (Gln) has long been known to be essential for cancer cell growth, which is generally thought to relate to the nutritional value of Gln as carbon and nitrogen source. On the basis of our recent finding that Gln provides acid resistance for E. coli through release of ammonia, we hypothesized that the primary role of Gln in cancer cells is to fight acid, rather than provide nutrition, through enzymatic deamidation. In this letter, we provide preliminary experimental evidence that supports this hypothesis. We demonstrate that Gln helps cancer cells survive acidic stress, which is compromised by inhibition of specific glutaminase activity. Our data suggests that glutaminase inhibitors, currently under clinical trials as an anti-cancer drug, may work by countering the ability of cancer cells to survive under acidic environment. We further speculate that the general requirement of Gln in cell culture is also due to its crucial role in acid resistance.

I think this is a big finding and if that is the case, in order to avoid lactate signaling and repress glutaminolysis we can apply one or multiple of the following strategies:

  1. Reduce blood glucose. This can be done
    • eliminate glucose or “to become glucose” ingestions by proper diet (i.e. restricted ketogenic diet or at least eliminate sugar, etc.)
    • reduce hepatic gluconeogenesis with e.g. Metformin, Berberine
    • reduce lactic acid conversion in the liver with Hydrazine Sulfate http://www.cancertutor.com/hydrazine/
      .
  2. Reduce glucose absorption by cancer cells:
  3. Inhibit lactate production
    This can be done by inhibiting various steps in the Glicolysis with e.g.

  4. Stop lactate export out of the cancer cells
    This can be done with teh help of MCT4 inhibitors, i.e. inhibiting the transporters responsible for lactic acid transport out of the cancer cells. Example of strong and accessible MCT4 inhibitors are:

  5. Eliminate lactate our of the body
    Neutralize lactic with highly alkaline substances e.g. 

  6. Stop lactate absorption by cancer cells
    If there is still lactate out there, in order to eliminate the chance for lactate signaling we can reduce their access to oxidative cancer cells. That can be done with MCT1 inhibitors such as:

    • Quercetin
      .
  7. Slow down mitochondria in cancer cells.
    If none of the mechanism above can be inhibited, than the last thing we can still do and be effective is to inhibit mitochondria which will otherwise require and process glutamine. Mitochondria can be targeted with e.g.

Interestingly, based on this lactate signaling view we can develop a treatments strategy that suggests using elements such as Metformin, already suggested to work well against glutaminosis. That is nice as it confirms this strategy may be oriented in the right direction.

References

Redox control of glutamine utilization in cancerhttp://www.nature.com/cddis/journal/v5/n12/full/cddis2014513a.html

Targeting Glutamine Induces Apoptosis: A Cancer Therapy Approachhttp://www.mdpi.com/1422-0067/16/9/22830/htm

A phase IIa study of PEGylated glutaminase (PEG-PGA) plus 6-diazo-5-oxo-L-norleucine (DON) in patients with advanced refractory solid tumors http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/2533

Glutamine Addiction: A New Therapeutic Target in Cancer http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917518/

 

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6 Comments on "Potential solutions against Cachexia: Glutaminolysis inhibitors and more"

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Moonlitnight
Member

This is very helpful, Daniel. Thank you.

Emad
Member

Doxycycline kills CSC !

I hope to see some statistics or trials about it soon

anna
Member

Very nice aricle!
My husband lost a lot of weight, and having good apetite cannot return to his previous weight.
He has also increased CO2 in blood, could it be due to lactic acid?

charkuyrkendall
Member

I am hoping my question will be answered sooner than later. Is it safe to combine DCA with hydrazine sulphate? I have my husband on DCA (he just started very recently) and he has cachexia. (He is also suffering from ascites – which I am looking into for thalidomide/celebrex combination).

So, is DCA/hydrazine sulphate okay?