Thursday, May 22, 2014

Flubbed The Obvious

I had an obnoxiously long blog post full of crazy information and charts, and things about glutamine - I had been working on it all day - then my mind was blown with a shattering epiphany, things started piecing together. If low grade tumors feed mostly off of glutamine/glutamate, then what's the story with glucose? So I talked it out with Dan and as we both started searching online (boy do we have some sexy phone dates) we finally started asking the right questions. What is in my special F-DOPA PET scan that I fly down to UCLA for? I felt like a moron, how had I never wondered that? If they weren't measuring glucose, which they clearly stated, what were they measuring? We typed it in and bam, if I'm understanding this correctly, the F-DOPA PET is essentially measuring an amino acid on the glutamine-glutamate pathway (click for a study).

How did I not ask that? How did I not figure it out? I remember being completely distracted by the fact that they were using radioactive particles. I guess that's where my mind went. It never occurred to me to wonder what was being mixed with those particles. I remember talking to my doctors after the surgery, in the neruosurgery ICU, about the idea of me going on the restricted keto to slow tumor growth. They thought it was great. How did it not come up that glutamine is the food source for my type of tumor, not glucose? Had they not pieced that together either? It seems as if they would have, yet, clearly they didn't or I think they would have said something. It's the whole point of this latest fancy scan, this exclusive machine that's only available at a few centers across the country, to measure the glutamine-ish stuff going on in my low grade tumor. How are the fragments of knowledge scattered so far apart throughout the tumor world that it's this hard for tumor patients to piece it together? What's going on? Oh, I feel sick. We really do have to figure stuff out on our own. Thank God I give a fart. At least now I can adjust. If I would have stayed on the Paleo diet it would have sped up tumor growth. The way that I have been eating has been full speed down the pro-amino acid freeway. No stoplights. And according to what I'm reading, the more glutamine in your system, the faster your tumor shifts into using glucose as fuel. It's a catalyst. Hello faster growing tumor. Hello death. I am literally glaring at an imagined Grim Reaper right now. I just told him I'm not ready, and if he comes near me he's going to regret it. Scythe or no scythe, this girl is scrappy.

Here's a scary, but necessary read about glutamine (for the record, I have shifted from Coldplay to straight up Enya's greatist hits - in dire need of some uplifting):


Glutamine promotes hallmarks of malignancy (click for full article)

Deregulated energetics. One hallmark of cancer cells is aberrant bioenergetics (26). Glutamine’s involvement in the pathways outlined above contributes to a phenotype conducive to energy formation, survival, and growth. In addition to its role in mitochondrial metabolism, glutamine also suppresses expression of thioredoxin-interacting protein, a negative regulator of glucose uptake (27). Thus, glutamine contributes to both of the energy-forming pathways in cancer cells: oxidative phosphorylation and glycolysis. Glutamine also modulates hallmarks not traditionally thought to be metabolic, as outlined below. These interactions highlight the complex interplay between glutamine metabolism and many aspects of cell biology.

Sustaining proliferative signaling. Pathological cancer cell growth relies on maintenance of proliferative signaling pathways with increased autonomy relative to non-malignant cells. Several lines of evidence argue that glutamine reinforces activity of these pathways. In some cancer cells, excess glutamine is exported in exchange for leucine and other essential amino acids. This exchange facilitates activation of the serine/threonine kinase mTOR, a major positive regulator of cell growth (28). In addition, glutamine-derived nitrogen is a component of amino sugars, known as hexosamines, that are used to glycosylate growth factor receptors and promote their localization to the cell surface. Disruption of hexosamine synthesis reduces the ability to initiate signaling pathways downstream of growth factors (29).

Enabling replicative immortality. Some aspects of glutamine metabolism oppose senescence and promote replicative immortality in cultured cells. In IMR90 lung fibroblasts, silencing either of two NADPH-generating isoforms of malic enzyme (ME1, ME2) rapidly induced senescence, while malic enzyme overexpression suppressed senescence (30). Both malic enzyme isoforms are repressed at the transcriptional level by p53 and contribute to enhanced levels of glutamine consumption and NADPH production in p53-deficient cells. The ability of p53-replete cells to resist senescence required the expression of ME1 and ME2, and silencing either enzyme reduced the growth of TP53+/+ and, to a lesser degree, TP53–/– tumors (30). These observations position malic enzymes as potential therapeutic targets.

Resisting cell death. Although many cancer cells require glutamine for survival, cells with enhanced expression of Myc oncoproteins are particularly sensitive to glutamine deprivation (8, 12, 16). In these cells, glutamine deprivation induces depletion of TCA cycle intermediates, depression of ATP levels, delayed growth, diminished glutathione pools, and apoptosis. Myc drives glutamine uptake and catabolism by activating the expression of genes involved in glutamine metabolism, including GLS and SLC1A5, which encodes the Na+-dependent amino acid transporter ASCT2 (12, 16). Silencing GLS mimicked some of the effects of glutamine deprivation, including growth suppression in Myc-expressing cells and tumors (10, 12). MYCN amplification occurs in 20%–25% of neuroblastomas and is correlated with poor outcome (31). In cells with high N-Myc levels, glutamine deprivation triggered an ATF4-dependent induction of apoptosis that could be prevented by restoring downstream metabolites oxaloacetate and α-ketoglutarate (15). In this model, pharmacological activation of ATF4, inhibition of glutamine metabolic enzymes, or combinations of these treatments mimicked the effects of glutamine deprivation in cells and suppressed growth of MYCN-amplified subcutaneous and transgenic tumors in mice.

The PKC isoform PKC-ζ also regulates glutamine metabolism. Loss of PKC-ζ enhances glutamine utilization and enables cells to survive glucose deprivation (32). This effect requires flux of carbon and nitrogen from glutamine into serine. PKC-ζ reduces the expression of phosphoglycerate dehydrogenase, an enzyme required for glutamine-dependent serine biosynthesis, and also phosphorylates and inactivates this enzyme. Thus, PKC-ζ loss, which promotes intestinal
tumorigenesis in mice, enables cells to alter glutamine metabolism in response to nutrient stress.

Invasion and metastasis. Loss of the epithelial cell-cell adhesion molecule E-cadherin is a component of the epithelial-mesenchymal transition, and is sufficient to induce migration, invasion, and tumor progression (33, 34). Addiction to glutamine may oppose this process because glutamine favors stabilization of tight junctions in some cells (35). Furthermore, the selection of breast cancer cells with the ability to grow without glutamine yielded highly adaptable subpopulations with enhanced mesenchymal marker expression and improved capacity for anchorage-independent growth, therapeutic resistance, and metastasis in vivo (36). It is unknown whether this result reflects a primary role for glutamine in suppressing these markers of aggressiveness in breast cancer, or whether prolonged glutamine deprivation selects for cells with enhanced fitness across a number of phenotypes.

I am mortified and kicking myself that this fell through my fingers. There is en masse of information out there about what to do, what to eat, how to survive cancer, and the hard part is that much of it contradicts. You never know which boat to jump on, but one thing is for certain you'll never survive long if you are stuck treading water. But how did I not follow the tracks? The obviousness of the F-DOPA; the uptake of an unknown substance that was allowing my tumor to glow on this special scan. How did I not think to ask what caused the illumination? I feel like a fool. It saddens me that I've spent a year and a half headed in the wrong direction, eating almost exactly what I shouldn't have. The nauseating irony. All this falls right before my MRI. I have spent the last four months eating glutamine rich foods, just nurturing old Hermie, pampering him. I've already called my doctor to get the ball rolling on adding sodium phenylbytrate (a plasma glutamine lowering drug) at my June 25th appointment - gotta sign some legal documents since it's off label. The crazy thing is that my team of nutritionists who specialize specifically in brain cancer patients were emphatic about me having protein with every meal, and snack, to keep blood glucose stable. The peanut butter was pushed to join in with the apple. But now I know, from checking the levels, peanut butter has a crazy high volume of glutamine. It looks like I would have been better off with just my original apple. How crazy is that!? It's so confusing.

I gotta go decompress. Time restart Enya's greatest hits or something. And maybe munch on one of those juicily tart apples.

Cool thing of the day: Earlier I got an email from Julene, a very sweet blog reader. We had never met, but she offered to drop off a care package to help me survive until Dan arrives (saving me from resorting to my mom's granola bars - definitely not on the new diet).

It was just what I needed. I met a new friend, I stole a few much needed hugs from her, and little did I know that vegetables were going to be paramount in my new diet. And apples have one of the lowest concentrations of glutamine in foods. Why wasn't I listening to my gut!?!? You guys know I love apples. Ugh. FOOL.


  1. Consider - glutamate is thought to trigger seizures in epileptics. Many epileptics respond very well to the ketogenic diet maybe because ketotic brain metabolizes glutamate differently, or more efficiently, than non-ketotic.

    1. Thanks for the note. I had recently been reading about the correlation of seizures and excess gutamate in the brain (while reading about the supplementation of taurine to aid in seizure prevention). I've done both the ketogenic and restricted ketogenic diets, but in the research a basic ketogenic diet actually feeds the brain tumors. It's negligibly better than a standard American diet, even equally bad in some studies ( So, with both issues, the seizures and the tumor, I have to focus first on slowing tumor growth, then hoping the seizures will lessen as well. The other thing about ketosis is that in order to do the restricted ketogenic diet you have to severely limit your overall caloric consumption. I don't mind the majority of my diet coming from fat, but with the 30% decrease of calories each day, it becomes harder and harder to have energy. Since I couldn't increase the vegetables, or plant matter, because it would kick me out of ketosis, the only other option is to increase protein, and that would therefore increase glutamate/glutamine and regardless of it being utilized differently while in ketosis, it would still theoretically feed the tumor. It's a complicated web, and I'm not convinced that I even understand it all, but I appreciate your input. Thank you for trying to help me figure it out. If anything else comes up, or you have more ideas, my ears are always open.

  2. hey jess, me again. some of my symptoms started returning this week which is 3 months post op, and then i read this and that i've been doing things wrong and it got me worried. now i've been vegan since surgery because of animal protein increase growth factors so i havent massively far off. but i've been eating lots of plants protein in the form of beans and seeds/nuts etc which all contain glutamine so now i know i've been doing a lot wrong.

    from what i can tell all protein sources have glutamine. even high protein veg like spinach and broccoli, so i'm really struggling with how to avoid it. obviously most fruits and vegetables are okay. but what is your diet going to consist of now?

    thanks for bringing this all up to light, i had completely missed it too.

    1. Oh no. I hate hearing about those symptoms. Ugh.

      I'm blown away by the concentration of glutamine/glutamate in all the various foods - this could drive us all crazy. Also the whole correlation between seizures and excess glutamate in the brain. How had I never heard that? Remember that calorie restriction seems to be paramount. So perhaps your grains and beans aren't so bad of you're CR. That's what I'm starting to focus on.

      I definitely haven't ironed out my diet, but it's looking somewhat like 70/10% plant matter (veggies/fruits respectively), 10% fats, 10% protein (from low volume glutamine sources). I'm just making it up as I go right now and holding to a 30% caloric restriction. We'll see how it goes, though because I'm already starving!!

    2. interesting you should say those ratios, in the raw food world there is a very popular diet called the 80/10/10 diet by dough graham and there is a girl who without surgery or any treatment shrank her own brain tumour with a diet of those ratios. her name was megan sherow i think, it wasn't an astrocytoma but a glial neuroblastoma so could account for it. i never went into the whole 80/10/10 because i liked weightlifting too much and it seemed like too many carbs, but saying that i know a few people who follow that diet and they are very athletic with no health problems. The WHO are actually fine with a 5% protein diet. i was using chickpeas as my main carb source due to them keeping blood sugar so low. that has to stop i suppose.

      fibre has the same balancing effect on blood sugar as protein so its not the end of the world. also if you're taking berberine it shouldnt be a worry anyway. how far can you take calorie restriction in a person like you whos already slim? fortunately for me i put on so much weight taking steroids that i have a lot of room to loose, but that can't go on for much longer. fortunately epilepsy already seems to have the low glutamate/aspartate diet which im just going to jump on for the time being.

      anyway, keep us informed when you come up with something, would be nice to know :)

    3. I'm going to look into that 80/10/10 (I had literally pulled my numbers out from under a rock - great to know I'm on the right track!). I'm blown away by the Megan Sherow story, that's so exciting! I'm going to see if I can find her on the interweb too.

      I don't think you have to give up chickpeas, maybe just cut back? Thank you for all of that info on the raw food, the ratios, and the comment about the exercising. I love working out, especially weight lifting too. I do take berberine (two pills with every meal) and I'm on metformin 500 mg bfst & din.

      I get the feeling that I'm going to have to do the 30% reduction of calories 5 days a week, then a baseline 1 day, and maybe a free day. (On that free day I won't go crazy, but I won't count.) That's just my basic thought for now to keep it manageable.

      You are already way ahead of the curve with diet, I think you're doing great. I mean that. I'm really impressed. I'm sorry about the symptoms, though. I'm keeping my fingers crossed that it's just your brain healing, and maybe stress?

  3. I need to chime in and add an important point - glutamate is the primary nitrogen donor for the synthesis of essential amino acids. The human body needs a certain amount of glutamine/glutamate, otherwise you'll go into protein deficiency. I think figuring out a baseline need for protein and stopping there is the key. 10% of calories as protein is probably a good target.

  4. Sorry, change "essential amino acids" to "non-essential amino acids" in the above comment. Non-essential amino acids aren't required in the diet because they can be synthesized using nitrogen from glutamate (ie glutamic acid).


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