Ketones, Cancer, and the NLRP3 Inflammasome
“Check ‘em all. Do the work. There’s no room for cherry-picking here.

LOOK THE GIFT HORSE IN THE MOUTH”

A few years back, researchers discovered the pseudo-ketone beta-hydroxybutyrate suppressed the NLRP3 inflammasome (Youm et al., 2015). NLRP3 is notorious for aggravating gout symptoms, so it was like: “Yay! A potentially clinically relevant use for ketone supps!” (I think there might be other applications as well, but that’s for another blog post).

Ketones, NLRP3, and IL-1b



It’s thought that NLRP3 is around during active flares, so gout sufferers would stay on their regular meds and take ketone supps as needed – this is important because from what I understand, gout flares really suck, some people get them frequently, and ketone supps aren't covered by insurance [yet?].



Besides certain aspects of the ketogenic diet, I’m also interested in “Ketone bodies as signaling metabolites.” From this perspective, ketones are quite interesting, interacting with circadian biology, HDACs, ChREBP, epigenetics, inflammatory pathways, etc., etc.



However, there may be a dark side, or rather a very large confusing gray area when it comes to ketones, cancer, and the NLRP3 inflammasome…

Remember that whole “keto-for-cancer-because-everything-is-Warburg” thing? ...it’s not really a thing (more on this below).



This paper showed NLRP3 is upregulated in a model of squamous cell carcinoma (ie, cancer), and an inhibitor of NLRP3 was effective. Cool, all pre-clinical & in vitro stuff, but maybe these researchers could test beta-hydroxybutyrate in their model. I say this because there are many different types of cancers, any potential therapeutic avenue should be tested in as many models as possible. In addition to beta-hydroxybutyrate, there are even a couple other NLRP3 inhibitors… which ones might work for which cancers, if any?

This study showed NLRP3 inhibition shut down colon cancer cells and this one for lung cancer cells…

AND TO MAKE IT ELEVENTY-BILLION TIMES MORE COMPLICATED

NLRP3 inhibition didn’t work in this study on a different lung cancer model. Ugh.

And this study showed NLRP3 was down in a model of liver cancer, and the lower the NLRP3, the worse the cancer. Since NLRP3 is already down, would beta-hydroxybutyrate do nothing? Could it make it worse?!

Begin mini-rant::
Check out this video with Drs. Norton and D’Agostino where besides a coherent discussion of #keto, Dr. D’Agostino describes how certain tumors actually thrive on fatty acids... Warburg?
To be fair, Seyfried and colleagues (including D'Agostino) recently published this comprehensive review which describes/expands/clarifies the Warburg[ish] theory in detail. Highly recommended. However, the overall tone is something like: "there can be no other way cancer arises. This is how all tumors form. There are no unknowns. And we have the cure..." While that may be a bit of an exaggeration and I'm certain there are more unknowns for me than Seyfried et al., my take is the usually more like: we may have figured one way it could possibly happen but need to test it way more times in a variety of contexts and there are probably loads of unknowns.
End Rant::

An NLRP3 inhibitor worked in this model of colon cancer, but this one showed colon cancer was better able to metastasize to liver in the absence of NLRP3. In some cases, NLRP3 may be necessary to kill tumor cells. I would not want beta-hydroxybutyrate anywhere near those cases.

#context



Cancer is a doozy. If you’re reading this for yourself, your patients, or someone you know, learn about the specific tumor type, then check how different therapeutics have worked in as many models possible. For example, there are literally hundreds of pre-clinical models of liver cancers.

Check ‘em all. Do the work. There’s no room for cherry-picking here.

LOOK THE GIFT HORSE IN THE MOUTH

In this #context, I’m more 100-to-1 than 51/49 (and even then, I'd look at that "1" pretty closely). Kinda like the opposite of cherry-picking.
Cherry-planting?

Warburg :(

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