there hasn't been much written about the role of glutamate in gliomas, so I was wondering if anyone had looked into it before? It caught my attention some time ago when someone posted a link to "medical food" Cronaxal, which "is a combination of oxaloacetate and ascorbic acid (vitamin C). Oxaloacetate reduces Glutamate levels in the brain in multiple laboratory animal tests. Glutamate overproduction is directly tied to the growth of malignant gliomas, their invasiveness, and their ability to destroy neighboring brain tissue. Patients with Glial Tumors have an impaired capacity to metabolize glutamate due to the high amount of glutamate produced by the tumor itself. Oxaloacetate helps to metabolize glutamate to alpha-ketoglutarate."
Anyway, search on pubmed does return some hits on glutamate and glioma, for example Glutamate and the biology of gliomas (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107875/) where it states: "Glioblastoma tumors release Glu to enhance their highly malignant behavior, and that Glu release via system xc- and the excess extracellular Glu this system imparts a survival advantage by promoting resistance to apoptosis and by promoting glioma proliferation and invasion. In fact, the invasive nature of gliomas enhanced by Glu release is one of the most important limitations to effective disease control; experience demonstrates that more than 80% of glioblastoma recurrences occur within 2-3 cm of the original resection cavity. Successful treatment of malignant gliomas requires recognition of Glu and its receptors as potential targets and novel approaches modulating their influence are needed to improve upon existing ineffective therapies."
At the end of the article there are some suggestions for targeting glutamate with repurposed drugs, but I also found some supplements that could do that in some degree (like theanine, N-acetylcysteine and glycine). Anyone tried this approach to complement the cocktail?
Sulfasalazine, a cheap drug first approved by the FDA in 1950, is an inhibitor of the glutamate-cystine antiporter, system xc, and can reduce the amount of glutamate being released by GBM. At a dose of 1 gram per day it can also inhibit seizure activity, which can be related to glutamate accumulation. I've added it to my A list, given its low expense and clinical evidence. See studies in folder 1, sulfasalazine subfolder of the brain tumor library.
ReplyDeleteCRONaxal of course has mouse evidence, which we discussed a little bit here:
http://btcocktails.blogspot.ca/2016/04/cronaxal.html#comment-form
Thanks for bringing this up Matjaz
I should add that this attribute of GBM (release of large amounts of glutamate via the glutamate-cystine antiporter) may not apply to lower grade IDH-mutant gliomas, which instead take in glutamate and convert it to alpha-ketoglutarate, and then to the oncometabolite 2-hydroxyglutarate by the mutant IDH1 enzyme.
DeleteDear Stephen,
DeleteCould Sulfasalazine be given in low grade glioma as prevention/treatment of seizures?NO advised levipil..
While there is some evidence of sulfasalazine as having anti-seizure effects in GBM ( https://www.ncbi.nlm.nih.gov/pubmed/24608453 - strong trend towards longer seizure-free survival in the sulfasalazine group), it might not be effective for low-grade IDH-mutant astrocytomas, which tend to release 2-hydroxyglutarate in large quantities, rather than glutamate.
DeleteThe main mechanism proposed for sulfasalazine is to prevent the release of glutamate by tumor cells through blocking the activity of the glutamate-cystine exchanger. This exchanger (System xc) is highly active in about half or more of GBMs. This mechanism of action of sulfasalazine would not prevent the accumulation of 2-hydroxyglutarate in IDH-mut low grade astrocytomas, which is similar in structure to glutamate, and also likely contributes to seizures.
In other words, IDH-mutant gliomas may be hungry for glutamate and release 2-hydroxyglutarate, while non-IDH-mutant GBM is hungry for cystine to manufacturer glutathione and releases excess glutamate into the extracellular space, where it contributes to tissue damage (excitotoxicity) and seizure activity. In IDH-mutant gliomas it is instead 2-hydroxyglutarate (converted from glutamine/glutamate) that accumulates and contributes to seizure activity. Glutamate and 2-hydroxglutarate are very similar molecules.
ReplyDeleteDo you think that lowering glutamate levels is also a viable option for IDH mutant gliomas - lower glutamate levels -> lower 2HG levels after conversion I guess ?
DeleteAccording to the literature, glutamate doesn't really cross the blood-brain barrier, so the glutamate in the central nervous system would have to be made from glutamine. It's far from certain that it would be possible to reduce circulating glutamine to an extent that it would affect 2-HG production by the tumors, as glutamine is a vital nutrient for the body. That may be possible but there's no evidence for it.
DeleteThe only really effective way I know of to lower 2-HG production would be one of the novel drugs that inhibits the mutant IDH1 enzyme (for example AG-120, or AG-881).
Another proposed strategy is the inhibition of glutamate deyhdrogenase 2, which is important for IDH1 mutant tumors to convert glutamate to alpha-ketoglutarate. Chloroquine has been proposed but unfortunately chloroquine is a preferential inhibitor of GLUD1, not GLUD2. See the section on glutamate dehydrogenase 2 on the page below.
http://astrocytomaoptions.com/exploring-strategies-for-idh1-mutated-gliomas/
Cronaxal was part of my husband's cocktail. There's no telling if his cocktail slowed progression, but it obviously did not keep things in check.
ReplyDelete