Glutamate, ROS and Endocannabinoids

At 7:40 in this video: https://www.youtube.com/watch?v=Cd5AYWX_bT4&t=1s he talks about how endocannabinoids block neurotransmitters such as glutamate. You can't see the slides which might make it more helpful but can anyone relate this is the usefulness of cannabis, especially as it relates to IDH1 mutated tumors?

I'm also trying to make sense of how ROS is thought to be related to glutamate? I thought I read that glutamate in IDH mutated tumors stops the cells from being overwhelmed by an influx of ROS and so that is why they are so glutamate hungry.

So my next thought is could a combination of cannabis and high dose vitamin c infusions, which is thought to also overwhelm the cells with ROS, be beneficial.

I have no idea if any of this makes sense. It's just overlap I'm seeing and so I thought I'd put it out there.

Maria

Cronaxal

Has anyone tried Cronaxal or might have any info regarding whether it is worth trying? Thanks
http://www.cronaxal.com

Glutamate?

Hello,

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 x_c^- 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?

 

Blocking BCAT1 and or Glutamate

Hi all
Wondering if any1 could help me.
My dad's pathology report stats that he has over expressed BCAT1 and is idh1 wild type.
I have been searching trying to find something that may be able to block this aggressive amino acid.
I have only found one paper paper to suggest that a drug may help it is an anti seizer med called gabapentin, has any1 took or used this before ?
BCAT1 is the reason wild type idh1 are more aggressive.
Also I was wondering if anyone knows of any know ways of blocking glutamate? As this is what fuels these things?

http://www.patentsencyclopedia.com/app/20150374800

Many thanks all

Glycine?

Hello all,

Stephen posted about Glycine at the end of November 2015 on astrocytomaoptions under Exploring strategies for IDH1 mutated gliomas. I'll just paste it here again. Anyway, does anyone have any experience with this supplement? It is fairly cheap and non-toxic, so was maybe anyone thinking about trying it?

Reversing hypersuccinylation

November 28, 2015
A research team at Fudan University, China, published a study [46] in the journal Molecular Cell, demonstrating a novel mechanism for the tumorigenic effects of IDH mutations. In this study, the oncometabolite 2-HG, produced in large quantities by mutant IDH enzymes, was found to competitively inhibit the activity of the citric acid cycle enzyme succinate dehydrogenase (SDH), leading to the buildup of succinate and succinyl-coenzyme A, and the hypersuccinylation of lysine. Lysine is an amino acid component of proteins. IDH1-mutated patient glioma samples were found to have significantly higher levels of succinylated lysine than IDH1 wild-type glioma samples, with the most intense succinylation being localized in mitochondria.
The effects of this mitochondrial hypersuccinylation were then examined. Overexpression of IDH1 R132H mutation in cells led to increased succinylation at succinylation sites in mitochondrial enzymes pyruvate dehydrogenase (PDHA1), succinate dehydrogenase (SDHB) and cytochrome c oxidase. The latter two enzymes are components of the electron transfer chain. Succinylation of these enzymes led to their decreased activity, causing impaired oxidative mitochondrial metabolism. Importantly, IDH1 R132H overexpression induced the accumulation of BCL-2, an anti-apoptotic protein, in the mitochondrial membrane. Reversing hypersuccinylation by genetic manipulations also reversed the apoptosis resistance of the cells.
The researchers then hypothesized that glycine may be able to reverse the hypersuccinylation found in 1DH1 mutant cells, as the condensation of glycine and succinyl-coenzyme A would send the resulting 5-aminolevulinic acid into the heme biosynthesis pathway, leaving fewer succinyl groups available to succinylate proteins. This was indeed found to be the case in vitro. Next, mice were subcutaneously xenografted with HT1080 fibrosarcoma cells, which harbor a naturally-occuring IDH1 R132C mutation. The mice were fed a chow supplemented with 5% glycine. Impressively, tumor weights in the glycine supplemented mice were 67% smaller than the tumors from mice fed the control diet, and succinylation levels were also lower, providing proof of principle of the glycine-supplemented diet.
Note, however, that a glycine concentration of 100 mM was used in vitro, far higher than the ~1 mM that is achievable in serum, even with very high glycine doses. The study did not exclude that tumor growth inhibition may have been primarily due to anti-angiogenic effects, as seen in melanoma mouse studies.
Glycine is an amino acid and neurotransmitter. A summary of the use of glycine as a dietary supplement is found at the website examine.com.

Mefloquine; Memantine; Metformin; Temozolomide

Dear all,
What do you think about adding the above medications to the cocktail? I was browsing trials on MDA site and ran across this one
http://utm-ext01a.mdacc.tmc.edu/dept/prot/clinicaltrialswp.nsf/Index/2011-0374
Quoting:

Temozolomide is designed to kill cancer cells by damaging DNA (the genetic 
material of cells). The damaged DNA may cause tumor cell death.

Memantine is designed to block the activity of a protein found on the surface 
of cells that may control tumor growth and survival. This may stop further 
spread of tumor cells.

Mefloquine is designed to block a protein that helps to clean the waste in the 
cells and to destabilize the cell membrane. Blocking this protein may cause 
tumor cell death.

Metformin is designed to block a protein in tumor cells that is important in 
tumor growth and blood vessel development. This may cause cell death or reduce 
the spread of the disease.

I already take Metformin and TMZ.  Have a chance to order Mefloquine and Memantine and wondering if I should. Is Mefloquine similar to Chloroquine?
Thank you!