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Answer to Manuel on Phenylbutyrate  


Member Admin
Joined: 5 years ago
Posts: 722
15/10/2018 11:58 am  

Hi Manuel,

I post here my answer to the questions you sent by e-mail as the content may be relevant to others.
I have two points to make:
1. Answering your question:
I think Phenylbutyrate is a good idea indeed. It was one of my preferred drugs but I had no chance to write about it yet. Regarding the mechanism, its not clear if the anticancer effect is due to action on mito, like DCA, or due to action on glutamine. 
Based on the profile of glioblastoma, its important to address the well known highly increased fermentation. On this line, I see two main strategies her:
a. Reduce fermentation and in more general ATP levels: Focus on reducing fermentation and mito activity to support chemo as a main focus (note that in some gliobalstoma mito may be inhibited already)
b. Reactivate PDH: Focus on redirecting metabolism to mitocontria while inhibiting fermentation (adding chemo too but here this is not the focus)
What is clear is that in both approaches, inhibition of fermentation is very important in glyoblastoma and should always be a central part of the treatment strategy.
Inhibit mito is good in combo with fermentation inhibition, but looking back at various substances used in glioblastoma also looking at activating some enzymes to push back pyruvate in mito (PDH/PDK) may be important.
What is less clear is what is the best strategy out of the two above to start with.
While now writing I realize it could be best to combine both strategies in one to make sure the following:
- fermentation is reduced
- also reduce mito activity (in case that is there)
- while making sure that a complete mito inhibition due to PDK is not the origin of cancer
Combining mito "inhibitors" such as Metformin with mito "activators" such as DCA or PhenylButyrate  does not sound logical. But in reality, at doses taken by humans e.g. Metformin will not completely inhibit mito, so that DCA or PhenylButyrate can still work.  Actually, it has been shown in multiple studies that Metformin works in synergy with DCA for example.
Based on this, I would indeed consider as a next step to try improving the current strategy the following:
- Keep TMZ chemo and use the strategy as you suggested (higher dose of chemo while on fermentation inhibitor you are currently using)
- Keep Metformin at this point (because it also helps not only acting on mito but also reducing blood glucose which feeds the fermentation otherwise)
- Add PhenylButyrate as it acts as DCA but it does not come with the side effects of DCA (DCA side effects are not there for many patients but for some could be enough to stop)
The more I think of it the more I realize that for glioblastoma it makes sens to try adding PhenylButyrate on top of strategies such as chemo+2DG+metformin, for glioblastoma.
AlphaLipoic Acid IV could do the same but it also comes with increasing antioxidant capability of the cancer cell which we want to avoid when on chemo.
Regarding your question about glucosamine, I actually think its a different discussion, but I would need to check (again) the science behind (as it acts on more aspects other than glutamine).
2. A few days ago I received info from a friend saying he knows glioma and glioblastoma patients using CRM197 and seeing great results
If there are general questions on the above, please write here. If there are personal, please write by e-mail.
Kind regards,