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