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Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR


Daniel
(@daniel)
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@Johan

We were speaking during the past days here about the cancer cells who "forgot to go to sleep". I found this paper that indicates exactly that, as a result of acidic environment. It's a very good and recent paper in a highly rated journal:

Acid Suspends the Circadian Clock in Hypoxia through Inhibition of mTOR https://www.ncbi.nlm.nih.gov/pubmed/29861175

Recent reports indicate that hypoxia influences the circadian clock through the transcriptional activities of hypoxia-inducible factors (HIFs) at clock genes. Unexpectedly, we uncover a profound disruption of the circadian clock and diurnal transcriptome when hypoxic cells are permitted to acidify to recapitulate the tumor microenvironment. Buffering against acidification or inhibiting lactic acid production fully rescues circadian oscillation. Acidification of several human and murine cell lines, as well as primary murine T cells, suppresses mechanistic target of rapamycin complex 1 (mTORC1) signaling, a key regulator of translation in response to metabolic status. We find that acid drives peripheral redistribution of normally perinuclear lysosomes away from perinuclear RHEB, thereby inhibiting the activity of lysosome-bound mTOR. Restoring mTORC1 signaling and the translation it governs rescues clock oscillation. Our findings thus reveal a model in which acid produced during the cellular metabolic response to hypoxia suppresses the circadian clock through diminished translation of clock constituents.


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 542
 

D, are you there? If we keep quiet, then we can work on a surprise for dng050.

I followed your link for the article above and then I started doing some other reading; I think I have found some things that could really help him. 

First, there is quite a bit of research that considers CTR1 (SLC31A1) and coppercarboplatin intake. Carboplatin uses the CTR-1 transporter to enter the cell as does copper. The more CTR-1 the more carboplatin can enter; there is a fairly strong correlation between tumor response and carboplatin intake. There is also research that describes how to up CTR-1 expression with TM, curcumin,EGCG etc.. That is an exciting first step. dng050 is lining up for carboplatin treatment, yet there is a way to amplify this treatment.

Second, there is a chitosan formulation of carboplatin that has been described that is ~300 times more effective than unformulated carboplatin. It would also be a great deal safer. nanocarbo? Wow! Basically, the nanoparticle with carbo would go to the cancer and the chitosan would melt away in the high acid cancer environment and be specifically delivered to the cancer cells. That could have a truly massive anti-cancer effect. 

There is also research describing genetics alterations that predict response of carboplatin in lung cancer as well as from your article in the supplementary tables the changes in gene expression that occur with acid and the circadian clock. Some well known ones are listed such as HK2 and MCT1. It would be amazing if cancer cells became highly vulnerable to intervention because of these gene changes.

The above is fairly remarkable. If we put this together for dng050, there could be an extremely powerful anti-cancer package.

 

 

 


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Daniel
(@daniel)
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Joined: 6 years ago
Posts: 1036
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@jcancom

Hi J,

You know that I very much appreciate your enthusiasm. But I think its best if we focus our discussions on the important scientific findings (and there is so much out there) and not on a specific visitor of this website, unless somebody specifically asks us for help with generating new ideas.

I think the reaction of Johan to the discussions on clinics is one that we should really consider. Whenever a friend that we value has such an intense reaction, it should be a sign for us that is the time to stop and reflect a little on our approach and see what we can improve. 

There is always space for improvement for all of us, and I think we should do our best to become better and better every day.

Exploring the science related to the dynamics of metabolism as a function of circadian clock is a very very interesting area. This is the type of subjects that we should focus on I think. 

On the metabolic line, another subjects that I find very interesting is Methyl Jasmonate. This is one of the subjects that I want to address on the Blog when I find time. Have you ever looked at Methyl Jasmonate? Whats do you think about it? Thank you!

Kind regards,
Daniel


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Jcancom
(@jcancom)
Joined: 4 years ago
Posts: 542
 

D, yes I looked at methyl jasmonate. It was surprising to me that some of the original researchers suggested that there might be toxicity problems with it. Typically, with natural type problems I have found that toxicity problems are often difficult to clarify. The real problem can emerge with chemicals such as salinomycin which can have significant problems with side effects.

 

I am thinking about the experience of adifer on the syrosingopine thread. What I find interesting is that there was such a large lactate response. The concern was that there would be lactate acidosis. I wonder whether there was an opportunity here. I am considering the Warburg trap concept. OXPHOS I inhibitors are known to upregulate glycolysis and cause more lactate to be produced and acidity the inside of cancer cells. With adifer there was a large effect of metformin on lactate production; i.e. greatly increased glycolysis. this implies that perhaps OXHPOS was especially impaired. If so, this suggests a strategy to take advantage of this; the Warburg Trap! The first part of the treatment is already in place: metformin. Now perhaps shift away from syro and move towards salinomycin (an ionophore). This is the dual combo suggested. The pHi is being greatly acidified by metformin and then the ionophore can help draw down ATP etc.. It would be good if we were able to observe the biochemical effects that we see and then select an appropriate treatment that can leverage any defects that the cancer might be showing. The high lactate level with metformin should have told us that the cancer had an OXPHOS problem.   

 


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