Sunday, November 22, 2009

Glucose, lactate and cancer

Here's an interesting paper, discussed in this editorial. Many cancer cells use glucose as their primary fuel. Under the hypoxic conditions, in the centre of a tumour mass, there is often a region where glycolysis is the only source of ATP with lactic acid as the main end product. This is quite old news, going back to Warburg and the concept of using low blood glucose to suppress tumour growth.

However, lactate is not a waste product. Lactate is an energy rich molecule which can be converted to pyruvate and so enter the mitochondria to generate a bucket load of ATP, given some oxygen. In fact there is a school of thought which suggests that brain neurons do not use glucose at all, glucose is converted to lactate by the astrocytes and it is lactate which feeds directly in to the neuronal mitochondria via pyruvate. It's controversial.

So lactate with oxygen is a potent combination for ATP generation. Oxygenated cancer cells burn lactate. They appear to love it. So the central anaerobic core generates lactate from glucose and the rest of the tumour feeds on lactate, so long as oxygen is present.

Lactate is taken up in to cells via the MCT1 transporter (mono carboxylate 1, it's a transporter for very small fatty acids, lactate being one of several). Inhibiting this transporter is bad news for lactate burning cancer cells and there are a number of drugs being developed along these lines.

What seems to happen when you block MCT1 is that the aerobic external layers of the tumour are suddenly deprived of lactate. They then turn to glucose for fermentation and in doing so deprive the anaerobic core of that particular source of usable energy. The cells in the anaerobic core die.

In the aerobic bulk of the tumour glucose can be burned via pyruvate in the mitochondria and there is no need for lactate production.

However lowering plasma glucose level when there is no longer any lactate available might provide a tool to use against this area of the tumour.

There is a very strong suggestion, certainly in rat brains, that ketone bodies inhibit the use of lactate. That's a physiological MCT1 inhibitor. Ketosis is usually (but not quite always) associated with low blood glucose levels. It is also associated with increased methylglyoxal production, an inhibitor of glycolysis.

So ketosis appears to provide the triple tools of MCT1 inhibition, glucose deprivation and glycolysis inhibition.

If it doesn't work against cancer, it should!

I hope Dr Fine has some success in his RECHARGE trial.

Peter

18 comments:

Nigel Kinbrum BSc(Hons)Eng said...

My liver used to be hyperactive at secreting glucose, resulting in fasting serum glucose of about 6mmol/L even on a low-carb diet. My last (Sept '09) fasting serum glucose was 5mmol/L. What changed? I've been taking 5,000iu/day of Vit D3.

I read a post on Nephropal about increasing Adiponectin level reducing Hepatic Glucose Production (& increasing glucose uptake) and that Vit D increases Adiponectin level.

Is this a possible explanation for Vit D's anti-cancer effects?

Matt said...

Wow, very excited about RECHARGE! I suggested to a colleague that he ask this son's oncologist about reducing sugar in his diet to help with his recently diagnosed esophageal cancer. The suggestion was immediately met with a negative response, and of course my colleague isn't going to pursue it further. Do you know if esophageal growths are affected by glucose as much as the other cancers they note?

Hans Schrauwen said...

Jimmy Moore recently held an interview with Dr. Thomas Seyfried talking about this exact same thing :

http://www.thelivinlowcarbshow.com/shownotes/wp-content/uploads/llvlc302-dr-thomas-seyfried.mp3

From an evolutionary point of view it makes sense : Hunter Gatherers would need need to able to survive several week long periods of no food.
This might have helped them 'clear out' unwanted growths.

I tried on all water fast for 4 days, it went better then expected (no hunger at all any more after 36h) but had to give up after I got kidney pain.

Gyan said...

So eating lots of coconuts will do something for the cancer?

I am personally invested in the breast cancer so it is not academic for me.

Peter said...

Gyan, I would suspect carb restriction might be needed too but coconut oil will ameliorate the signs of Alzheimers without carb restriction. This sounds as implausible as coconut oil helping in cancer, but why not? Of course there should be minimal cancer in coconut based societies if it were truely effective in a mixed diet. No information on that.

Hans, I'm getting to post on the +/- of ketosis next. This is a relevant comment. I've had information off blog about a reader's personal sustained fasting too, which is very interesting from the GI upset aspect, rather than kidney pain.

Matt, no info. But if the cancer is GERD related there is then a history of carb intolerance of some sort going on. But talking to oncologists is generally not terribly productive...

Nigel, maybe. But I also see many cancers as being the result of chronic inflammation and Vit D down regulates lots of genes related to inflammation... Far to early to do more than wild speculation. And hyperglycaemia upregulates pro inflammatory genes too. So yes, maybe!

Peter

TedHutchinson said...

Readers who want to understand a little more about
How to Optimize Vitamin D Supplementation to Prevent Cancer
can download a non copyright version of Veith's paper here.
The secret to keeping the proliferative and anti proliferative forces in balance is to keep levels both high and stable.

Hans Schrauwen said...

Peter,

thanks, looking forward to your next post. Myself I'm a believer that (most) humans need to be in full ketosis (all glucose left the body and it now only runs on ketones) for a couple of weeks per year.
Typically in the wintertime to coincide with less light and thus more sleep for full maintenance and repair.
But you probably should not run on ketones all the time.

However each time I go into ketosis even mild ketosis, my kidneys start to hurt. I'm not sure why this is and I'm not sure that if I continue it would get better and stop or it would just get worse.

Did you listen to Thomas Seyfried's interview. What is your thought ?

Peter said...

Hans, yes. I think he has to be respected but it is very hard to see where hard facts blend to very informed opinion. Fasting a fully healthy person might also not be quite the same as fasting a metabolically injured human. Cats fast in the wild if hunting is bad. Starving an obese moggy can precipitate hepatic lipidosis with a frequenly fatal outcome...

As a religious aside, Kwaniewski is VERY anti-fasting. Injured people need calories to repair. While he's a maverick he is very experienced in working with rather sick people. And of course he just says it is so, without further explanation...

Peter

Peter said...

Ted,

Thanks. I'm thinking about a D post. That will be a useful read through today...

Peter

Peter said...

Ted, I'm having trouble reconciling the labeling on Figure 3 and Figure 4 (are you having the same issues? Tissue vs renal enzymes, the ref is undoubtedly renal enzymes, not tissue), but I get the general principle and what he's trying to say. The whole paper is very interesting and has a lot to say about inland HGs eating animals while dressed in furs during cold climate conditions. Not a huge amount of D there...

Peter

TedHutchinson said...

In the paper Vieth says "I have shown that renal 1-OHase and 24-OHase do adjust according to 25(OH)D supply . However,adaptation of non-renal tissues to moderate change in serum 25(OH)D has never been characterized. The only thing known is that the vitamin D hydroxylases outside the kidney do not respond to PTH or to calcium"
Vieth goes on to explain his hypothesis to explain the Modeling of Tissue 1,25(OH)2D Levels during Declines in 25(OH)D

Although the paper was published in September 2009 it would have been written earlier. Such is the pace of Vitamin D research that there may now be better answers to your point and further support for Vieth's proposed modelling.

TedHutchinson said...

I've just heard from Dr. Reinhold Vieth who has pointed out that the draft copy of the paper I put online was in fact a Galley copy that has some very minor stylistic errors in it. and therefore is subject to copyright.
If it helps he also says

"Nobody has measured tissue enzymes under different prevailing 25D levels, but if there is any sort of regulation, the peripheral hydroxylases should behave similarly to the renal enzymes that we did measure."

Richard Nikoley said...

Late to the party here, Peter, but since there was some mention of fasting, wondered if anyone had heard about this:

http://www.physorg.com/news126202490.html

Basically, the idea is that after several days of fasting normal cells go into a different mode that makes them far more resistant to the ravages of chemo, such that instead of a simple 1:1 war of attrition, you get kill rates upwards of 20:1 cancer cell vs. normal cell.

Jeff said...

Hi Peter,

Any thoughts on this? I can't get paper yet. Still need to see study but I am not surprised. Tumor cells, unfortunately, almost always find away around selection pressures such as treatment interventions.

Peter said...

Hi Jeff,

Should there be a link there?

Peter

mehitabel said...

I could use some clarification.

"There is a very strong suggestion, certainly in rat brains, that ketone bodies inhibit the use of lactate. That's a physiological MCT1 inhibitor"

http://www.sciencedirect.com/science/article/pii/S0197018600001029

"Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain"

Peter said...

Hi mehitabel,

Yes, this is incorrect. Lactate is coming out of the brains under ketosis, not going in. The extra lactate is coming out of the brains due to continued glycolysis but with inhibition of glucose uptake in to the mitochondria induced by hyperketonaemia. Thanks for pointing this out.

Peter

TedHutchinson said...

Targeting metabolic transformation for cancer therapy
Might-o'chondri-AL put this link on Dr Davis's blog a few days ago.
It may interest readers of this thread.