Sugar depleted diet is not a cure for cancer

One of the ideas that circulate among proponents of alternative therapy for cancer is that cancer thrives on sugar and because of this, cancer can be starved to death by avoiding to eat sugar.

It is claimed that the idea is backed up by hard core science – the Warburg effect, which landed the discoverer the Nobel Prize.

Today we know and understand that things are more complicated than that.

In this post we will attempt to simplify the biochemistry/physiology involved and explain why the idea of a sugar depleted diet as cancer treatment doesn’t work in the real world.

What is sugar?

When we think about sugar, most of us think about the white powdery substance that is used to add a sweet taste to various foods. But it is a bit more complicated than that. The white powder is a compound called sucrose, which is chemically bonded glucose and fructose.

We also ingest sugar in other forms. Lactose for example is present in milk, and is chemically bonded glucose and galactose. Starch found in vegetables and seeds are large molecules made of chemically bonded glucose.

Details of sugar chemistry and manufaction is outside the scope of this post, but here is a good site if you are interested.

What do cells meet when they meet ingested sugar?

The sugar we eat (or drink) is not absorbed by the body just like that. It has to be broken down  to its building blocks first. So for sucrose to be absorbed it has to be split into glucose and fructose, which are then absorbed into the body.  Lactose is split into glucose and galactose etc.

So the the cells are exposed to these small building blocks  – or monosaccharides if you will  (glucose, fructose etc.) – regardless of the food source.

For the remainder of this post we will focus on glucose, because glucose metabolism is what the cancer-feeds-on-sugar myth is about. But it should be clear by now that cells do not distinguish between glucose from refined white sugar or glucose from other food sources.

What does a cell do with glucose?

Glucose is a major source of energy in the cells. This happens through a series of chemical reactions, where the energy in sugar is transformed into a compound that the cells can use.

This compound is called ATP. It’s a fancy word, but just think of it as the currency of energy. The more ATP, the more energy.

Glucose is also a major source of building blocks used in synthesis (construction) of other molecules that the cells need.

Inside the cells, there are three consecutive separate systems, which gradually break down the glucose molecules, thus harvesting the energy contained as well as building blocks for other molecules. These three processes are called glycolysis, citric acid cycle and oxidative phosphorylation.

It is beyond the scope of this post to go into details about these processes, but if you are interested, you only need to follow the links. We will just list a few important points.

• Glycolysis happens in all cells.
• Citric acid cycle and oxidative phosphorylation only happen when oxygen is available.
• Glycolysis generate 2 ATP molecules per glucose molecule.
• Citric acid cycle + Oxidative phosporylation – 28 to 30 ATP molecules per glucose molecule.

So the energy that can be retrieved from a glucose molecule is far greater when oxygen is available compared to lack of oxygen.

When oxygen supply is insufficient, the end product of glycolysis (pyruvic acid) is transformed into lactic acid, which accumulate in the tissue. You may have experienced this yourself during exercise. The muscle ache that develops is a result of this.

Where does all this talk about the Warburg effect fit in?

Otto Warburg looked into glucose metabolism in cancers, and he observed correctly that cancers produce energy predominantly by glycolysis (with accompanying production of lactic acid) – even when oxygen is available. Far from all the energy that could be harvested from glucose is actually harvested and as a result, the amount of glucose used by cancer is very high (up to 200 times normal). This is called the Warburg effect.

So the production of building blocks happens at the expense of a less efficient energy production.

This phenomenon has practical use today. In a PET-scan, areas of glucose uptake is visualised. And because of the Warburg effect, cancers are (often) seen as areas of high level of glucose uptake.

The Warburg affect is no reason to assume  that a sugar depleted diet is the cure for all cancers

The simplicity of the concept makes it easy to understand why people find it plausible that a sugar depleted diet kills cancer cells.

But since Warburg made his discovery, at lot more about cancer biology  as well as normal biology is understood. Let’s outline a few main points, and then decide if the theory is as plausible as it sounds.

1) Cancer is not a ball of cells that are identical in every aspect.

Not only is there large variation between cancer cells, but they also interact in very complex ways with the normal cells that are components of the tumour as well. The complexity of this interaction is illustrated below. It is a figure in  in this (very technical) article.

None of this was known to Warburg, and none of this is addressed by people who advocate sugar depletion as an alternative cancer treatment.

It has been established that:

• Not all cancer cells within the same tumour exhibit the Warburg effect.
• Sometimes it is the normal cells within a cancer that exhibit the Warburg effect.

2) Warburg effect can also be observed in normal cells outside the setting of cancer.

Cells of the immune system and stem cells also exhibit the Warburg effect. So shutting down cells access to sugar is certainly not going to strengthen the immune system. And it will not help the body when it needs to use stem cells to replace old worn out cells.

Inflammation (with the accumulation of cells of the immune system) is a well known source of false positive PET scans.

3) Some types of cancer do not show up on a PET-scan.

This suggests that some cancers do not exhibit the Warburg effect.

4) Glucose degradation is not the only kind of metabolism that takes place inside a cancer cell.

It has been established that fatty acid metabolism and breakdown of Glutamin are very important in cancer cells.

5) Glucose is stored as glycogen within the body

When more glucose than the body needs is ingested, glucose is stored as glycogen. Glycogen production happens more or less in most cell types, but the muscles and liver are the major sites of glycogen stores. When needed, the glycogen is transformed into glucose again.

The stores in the muscles are used by the muscles, while the stores in the liver is used to maintain a stable level of glucose in the blood (which is where the cancer as well as the rest of the body gets its glucose from).

6) Glucose can be made from scratch from other other molecules.

Quite a number of molecules can be used to produce glucose. The most important are lactate, glycerol and alanin (an amino acid = a building block of protein). Most other amino acids and some types of fatty acids can also be used. This is very important, because this helps the body maintain a fairly stable blood glucose level regardless of dietary supply. This graph shows what happens to the blood level of glucose and other substances during starvation:

The blue line shows that the blood level of glucose does decline, but glucose never disappears completely. The red line shows that the level of ketone bodies increase. Ketone bodies can be used as an energy source instead of glucose. But in contrast to claims, ketone bodies cannot completely replace glucose. At most ketone bodies may deliver up to 50% of the brains energy supply. The rest comes from glucose. So a complete elimination of glucose from the blood is incompatible with life.

If you are interested in further details, this article is recommendable.

Have scientists at least explored the possibility of attacking the Warburg effect?

The answer is yes. With a high rate of glucose consumption by many cancers, it is not difficult to understand why researchers want to know if this is a mechanism that could be attacked, and perhaps improve cancer treatment further.

In principle there are two useful ways that this mechanism could be attacked:

1) Reduce/eliminate intake of glucose intake through diet.

This is an idea that has been researched and is being exploited in some types of alternative cancer therapies. The principle is that a low supply of dietary glucose eventually leads to a degradation of fat into fatty acids and ketone bodies instead of glucose degradation. This type of diet is called a ketogenic diet. However a ketogenic diet or even a completely sugar deprived diet cannot completely eliminate glucose from the blood. Furthermore ketone bodies cannot completely replace glucose as fuel for the brain. Ketone bodies may deliver up to 50 % of the brains energy supply. The rest comes from glucose.

Most of what we know about the effect of a ketogenic diet on cancer comes  from animal experiments, but there is some evidence from experiments on human cancer patients too:

In one study, the researchers compared the effect of a ketogenic diet and a glucosed based diet respectively in 27 patients who had cancers of the digestive tract. They measured the proportions of cancer cells that were dividing in each group. If a ketogenic diet was effective, you would expect a lower proportion of dividing cancer cells in samples from this group. They couldn’t detect any statistically significant differences.

In another study, the researchers were interested in the quality of life of 16 patients with advanced metastatic tumours and no conventional therapeutic options. The patients were placed on a ketogenic diet which was intended to last for three months. They found:

• 1 Didn’t tolerate the diet and dropped out within 3 days
• 2 Died after 2 and 5 weeks respectively
• 1 Stopped after 2 weeks due to personal reasons
• 1 felt unable to continue the diet after 4 weeks
• 5 Stopped after 6,7 and 8 weeks respectively because of cancer progression
• 1 Had to discontinue after 6 weeks to resume chemotherapy
• 5 completed the 3 month ketogenic diet period

The latter 6 reported an improved emotional functioning and less insomnia, while several other parameters of quality of life remained stable or worsened.

A case report on 2 patients with a type of brain cancer called astocytoma was encouraging. One of the patients did improve, and the cancer didn’t progress for 12 months.

Clinicaltrails.gov lists several trials looking into this.

So a ketogenic diet may be beneficial to some patients, but it is not a cure for cancer.

2) Medication that interferes with the Warburg effect.

Discovery of new aspects of cancer biology opens up new possibilities for development of cancer destroying drugs. The Warburg effect is certainly an interesting possibility. One such drug under investigation is called Dichloroacetic acid commonly abbreviated as DCA. The mechanism is that shifting from aerobe glycolysis (ie. the Warburg effect) to citric acid cycle + oxidative phosphorylation promotes self destruction of cancer cells through apoptosis.

There are claims put forward by proponents of alternative cancer therapies that this is an effective treatment for  all cancers, and that it is backed up by research done in Canada.

There have been promising results in cell cultures and rodents. But not in all cancers. In one study researchers found that DCA decreased rather than increased apoptosis under hypoxic conditions. This translates into that DCA protected these cancer cells instead of destroying them.

But still the findings in cell cultures and rodents have been sufficiently promising to proceed to testing in humans.

A study including five patients with glioblastoma multiforme (a type of brain cancer) was published in 2010. These these patients also had various other types of treatments, so the study doesn’t really say anything about the efficacy of DCA.

Other misunderstandings in alternative cancer therapy related to the Warburg effect.

As explained above, the Warburg effect is about degradation of glucose resulting in production of lactic acid in the presence of oxygen.

A) Lactic acid

The production of lactic acid leads to a low pH (acidic environment) in the vicinity of the cancer cells. This phenomenon has lead to the reasoning behind some alternative ideas, namely that cancer can’t thrive in an alkaline environment.

The production of lactic acid inside the cancer cells causes an excess of hydrogen ions which will decrease pH inside the cancer cell. Cells, cancer cells as well as normal cells, can’t live with a low pH inside. For cells (including cancer cells) to be able to maintain their lives, they have to get rid of these excess hydrogen ions. There are numerous transport mechanisms that help cancer cells do just that. The extrusion of hydrogen ions leads to a lower pH in the vicinity of the cancer, but this is a result of what goes on inside cancer cells and not a condition for cancer cells to survive!

B) Oxygen

The phenomenon that glucose is degraded through glycolysis without proceeding through citric acid cycle and oxidative phosphorylation even when oxygen is available has inspired the idea that oxygen is toxic to cancer cells. Some quacks advocate use of hyperbaric oxygen chambers for prevention/treatment of cancer. Some even claim that Otto Warburg was awarded the Nobel Prize for the discovery of this, and this is supposed to prove them right. But we have already explained what it was that Warburg discovered – no need to repeat.

It is correct that too much oxygen is toxic to cancer cells. But too much oxygen is just as toxic to normal cells. If you are interested in further details about the damage too much oxygen can do to the body, you may find this wikipedia entry informative.

What are the main conclusions?

• Cells don’t distinguish between glucose (a sugar) from different sources
• Large amounts of glucose are often – but not always – used by cancer cells
• Large amounts of glucose are sometimes used by normal cells
• Consequently, a sugar depleted diet is not a cure for cancer

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