Understanding the Glycolytic Side of Cancer
I have been unclear about an aspect of glycolysis for some time, any comments that others might offer me about this would be greatly appreciated.
What I am concerned about is the fact that in an hypoxic region glycolysis would be expected to be highly expressed. In fact, here is my concern, in an hypoxic region glycolysis would be the only energy pathway that could be expressed. If oxygen were absent then there would in fact be no potential for OXPHOS to occur. OXPHOS is an obligate user of oxygen.
Perhaps when we speak about how FDG PET scans pick up the excess use of glucose by cancer cells what is actually being referred to is the excess uptake of glucose in these hypoxic regions. In hypoxic regions as noted above, glycolysis is the only potential energy pathway.
This then leads me to contemplate what would the displayed phenotype of a cancer that lacked such hypoxic regions? It would be very interesting to know what cancer could become without hypoxia. On the compass thread there was mention of a bacteria that could grow and destroy those cancer cells that were in hypoxia in lab models. What would happen then? Perhaps the main bulk of the tumor mass would no longer be present? Perhaps most of the lactate would no longer be produced? It is true according to the Warburg hypothesis that cancer cells can be glycolytic even in the presence of oxygen, though with hypoxia, cancer cells are obligate anerobes.
Removing the glycolytic cancer cells with metabolic treatments leaves cancer cells with OXPHOS ability. Yet, these cells have different properties: for example, they are less proliferative, etc. This line of thinking has been quite an insight for me. Cancer cells have much less freedom of resistance than I had believed. If you remove glycolysis, they are already confined to only one resistance path: OXPHOS which is not a high proliferation state for cancer.
I believe that if we force cancer cells into OXPHOS we could stabilize most of the problem (people living an almost normal life) until we reach the point in which we have an understanding of the cause(s) of each particular presentation. The more I think about it the more clear it gets. I support various treatments thinking about how to force cancer cells into OXPHOS and so producing free radicals that normal cells will easily tolerate but would devastate Cancer Cells, among them: the treatment of Dr. Berkson with alpha lipoic acid (forcing pyruvate into Krebs Cycle), Dr. Halabe with citric acid inhibiting PFK (and the addition of Hydroxycitrate to keep it inside the mitochondria) and Dr. Budwig because it addresses inflammation and mitochondrial membrane regulation (( http://dx.doi.org/10.1155/2014/709828, https://doi.org/10.2217/clp.11.34)) (The incorporation of four linoleic acid side chains in the same Cardiolipin molecule renders it the primary target of the attack by free radicals, causing its peroxidation. Mitochondrial CL peroxidation appears to be an early event preceding the intrinsic apoptotic cell death. Because its role in apoptosis and mitochondrial function, CL levels, and CL peroxidation have been implicated in several diseases such as cancer). At first, I thought Dr. Budwigs approach was just for not so aggressive cancers but the more i study it the more i believe it should be the core treatment.
Glycolisis inhibition with 2-DG is a great strategy thinking of the metronomic dose and implementing lipoic acid and ketogenic diet during treatment and Budwig's ideas along with on days out of treatment would be a great way to fight
One other aspect I think we need to address from a metabolic point of view are the Fibroblasts and their contribution in maintaining the survival of the tumors specifically at the edges where fibroblasts are located, fueling tumors https://www.liebertpub.com/doi/full/10.1089/ars.2016.6750
Because of multiple survival mechanisms of cancer cells, because multiple types of populations and because we can never suppress fully the cancer cells from a metabolic point of view, I think metabolic treatments alone may not be the complete answer to cancer, at least not to all cancers. However metabolic treatments
- are an important part of the answer, and represent essential tools when fighting cancer, that when combined with other treatment approaches may help find the answer to cancer
- and like Yudaiteska said above, metabolic treatments can also be used as tools that may help make cancer a chronic and not terminal disease.
While writing here I realize that it could make sense for us to have a specific post dedicated to Metabolic treatments in general and our understanding at this point on their role in cancer treatment strategies.
Yud, yes I have been thinking along the same lines.
For quite a while I was very worried when people would say "Well if you knock down glycolysis, cancer will simply resist by becoming more oxidative. Yet, in a recent article that I read about calcium pumps, what they found when they evolved the cancer cells from glycolytic to oxidative was that the oxidative cells were less proliferative. If you have to go through the whole glyclysis and OXPHOS pathway it takes longer and you can no longer shunt through the Pentose Pathway or expel lactate. Forcing cancer to become more oxidative is a victory in itself. You could then go in with a specific OXPHOS inhibitor such as Methylglyoxal and the cancer cell is completely trapped!
The great thing when thinking of cancer as a metabolic disease is that there really is no easy escape routes. There is only glycolysis, Crebs and OXPHOS. Metabolic thinking greatly simplifies a very complex problem.
I would love to see more references of mouse models that had a purely oxidative cancer phenotype. I would think that bulky, disfiguring and painful tumors would no longer be present. Oxidative cancer would need to exist within the context of mostly regular blood vessels (i.e., no regions of hypoxia).
D, suggested to start a list for anti-glycolytics here.
This looks like a good reference to get the conversation started. PMID:22684868
Others on the forum HELPP!!!! Any other ideas would be greatly appreciated.
Once the list starts to build up, I will make a list in a file format so that the information will be in an easy to use format.
HI J, please post link instead of PMID numbers ... most of the people are not going to type that again in Google. Here we have the link now https://www.ncbi.nlm.nih.gov/pubmed/22684868
I have been thinking about other glucose like sugars recently. I would love to find something that consumed an extra ATP when entering the cell, or needed even a little bit more processing effort. With the extreme nature of cancer's glycolytic overdrive almost anything like that could be highly effective as an anti-cancer treatment. I think I recently posted an idea about glycerol (?) that had such a property. Here's another: mannose. It would be comforting to know that all of these sugars had been investigated, otherwise one worries that yet others might still be left unfound.