Ketogenic Blog Series Part II 

Part II - The Ketogenic Diet and Cancer Cell Metabolism

Before and after pics are one of the most motivating parts of any diet.  

Let's be honest...if we don't know what we're going to get out of a diet, we're a lot less likely to stick with it.  When we can take a glimpse into our own future by seeing the successes of others, it's super motivating.  

Having said that, the most important changes aren't our looks; comparing how we look to how we want to look.  It's the unseen changes that happen from a diet that are the most important.  It's millions of small interactions at the cellular level that add up to big body changes...and the motivational selfies.

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In today's post, we're going to go over the applications of the ketogenic diet when it comes to cancer.  That means that we need to talk about some changes that cells go through on a very small, very intricate level.  

Full disclosure?  This might get a little bit complex...but I want to show that there's more reason to stick with the ketogenic diet (if it's something that your doctor thinks would benefit you) than simply changes you might see in the mirror.  

Remember, the proposed mechanisms through which keto exerts its anti-cancer effects aren't anything that you'd ever be able to see with the naked eye.  Today's post will talk about how keto interacts with cancer and some studies to show its efficacy.  

In case you missed it and need to know what the ketogenic diet is, and answer some questions about it, check out Part I of our Ketogenic Blog Series.

 

The Ketogenic Diet and Cancer Cell Metabolism


To understand how the ketogenic diet could potentially have anti-cancer effects we need to talk a little bit about normal cellular metabolism vs. cancer cell metabolism. 

Our entire body is made up of cells.  Even though the cells of different systems may hardly resemble one another, they are composed of the same basic parts.  Inside every cell is a nucleus and organelles, (ie small organs) that have individual functions.  These organelles are suspended in a fluid known as the cytoplasm.  The cytoplasm is more than just fluid though; it's a place where numerous enzymatic reactions occur.

One of these reactions is called glycolysis, which literally means the breaking down of something sweet, which breaks down glucose (sugar) into two molecules known as pyruvate.  These pyruvate molecules are transported to an organelle called mitochondria (colloquially known as the powerplants of the cell) where they go through numerous biochemical processes where oxygen is consumed, and carbon dioxide and energy is produced.

Basically, the cell says "Thanks for giving me some glucose, I'm going to turn it into pyruvate, and then I'll turn that pyruvate into energy I can use".

 Dr. Otto Warburg

Dr. Otto Warburg

In the 1920’s Otto Warburg, a Nobel prize-winning scientist, and one of the most prominent biochemists of the 21-century observed that even in the presence of oxygen cancer cells ferment glucose (26).  This is different from normal glycolysis where pyruvate and oxygen are consumed and energy is produced without fermentation.

By the way, this process of cellular fermentation is the same that produces your favorite fermented foods such as sauerkraut and pickles.  That's great for sandwiches, but not so much for your body.  Why?  As sugars are consumed and fermentation occurs, an acid is produced as the end product.  In the case of human cells, the end product is lactic acid.  

That's a key difference.  In normal cell glycolysis, acid is not produced as a byproduct.

Dr. Warburg's findings were interesting because fermentation is an archaic process...meaning that some of the most ancient life on Earth, such as bacteria, rely on fermentation as a means to produce energy.  Normal human cells produce very little energy using this pathway.

Upon further study, Dr. Warburg found that many if not all cancer cells had some inability to use oxygen to produce energy due to their mitochondria being damaged (21).  Because of that, cancer cells undergo aerobic glycolysis (the fermentation of glucose in the presence of oxygen that we were just talking about), which has become known as the Warburg effect and is a cornerstone of the metabolic theory of cancer (21).  

The fermentation of glucose is a very inefficient process that produces significantly less energy than if oxygen was used.  Therefore, cancer cells need to use much more glucose to replicate. 

Here's a question though, why do cancer cells ferment glucose for their energy if it's such an inefficient process?  There are numerous reasons, all of which can explain some of the behaviors that cancer cells exhibit.  

First off, cancers can grow pretty quickly.  So quickly, in fact, they can outpace the growth of blood vessels that would support and feed tissue in normal circumstances.  That means that in some instances, cancer cells can at times have only very limited access to oxygen.  In normal circumstances, that would lead to cellular death; however, the lack of oxygen, in this case, doesn't inhibit cancer cell growth (11).  

The second reason is that lactic acid is produced as the end product of glucose fermentation.  Why is that important?  Have you ever heard someone say "cancer can't live in an alkaline environment"?  It's a statement that I've heard many times, however, what people might not realize is why that statement is so common.  As cancer cells ferment glucose, lactic acid is pumped out as a byproduct, which leads to the acidification (the opposite of alkalinization) of the area around the tumor (11).  This acidic tumor microenvironment favors tumor invasion and also inhibits the immune system (11).  Furthermore, cells around the tumor can take up this lactate and from it produce pyruvate which, as previously discussed, is fuel to the cancerous cells (11).

If your head is spinning and you're wondering what the point of all this is, here you go:

The ketogenic diet is a very low carb (and ideally no overt sugars).  That means that the ketogenic diet limits cancer cell's access to glucose.  Since we've just identified glucose as a cancer cell's preferred energy source, and one that it needs more of than a normal cell (because of how ineffecient glucose fermentation is)...it's starting to make sense.  Add in the fact that on the ketogenic diet, the body switches from glucose to ketone bodies as fuel, and that cancer cells only function sub-optimally on ketones, (20) it's a double-hit on cancer cell function, activity, and resiliency.

cancer cells are opportunistic scavengers and can run on numerous fuel sources

Side note
It must be noted that there is research showing that cancer cells can potentially use ketones as a fuel source (312).  

However, it is well known that cancer cells are opportunistic scavengers and can run on numerous fuel sources such as fatty acids, glutamine, and various other amino acids.  What cannot be overstated enough is that the ketogenic diet is not a cure for cancer, but instead is a therapeutic tool which may help manage and potentially shrink tumors.

 

Other Proposed Anti-Cancer Mechanisms of the Ketogenic Diet

It is well documented in the literature that individuals on a ketogenic diet program consume fewer calories (618) than their usual normal.  This could be because of the appetite suppressing effects of the ketogenic diet, such as the satiating effect of increased protein consumption, the neuro-regulation of hunger signaling, and the fact the beta-hydroxybutyrate, may directly suppress appetite (23, 17).

Getting back to cancer, studies have indicated that a reduced calorie diet may be important in order to prevent cancer as well as to provide a therapeutic role in cancer treatment (Brandhorst and Longo., 2016).  Furthermore, it is well known that obesity in patients with cancer leads to increased adverse outcomes, and a ketogenic diet is very effective at reducing and controlling weight (6)

Another proposed benefit of the ketogenic diet is that it has been found to increase the efficacy of conventional therapies (1).  Additionally, it has been found to reduce the side effects from conventional therapy (16).  

Let's re-state that because honestly, it's huge.  The ketogenic diet has been found to increase the efficacy of conventional therapies (such as chemotherapy, radiation and biological agents).

Once again, the exact mechanisms are not yet known, but it is likely that there are numerous.  

One area of research that looks especially promising is the synergistic effect of radiotherapy and the ketogenic diet (10).  Doctors Thomas Seyfried and Dom D’Agostino, two leaders in the field of the metabolic theory of cancer, have proposed a press-pulse framework, in which ketogenic diets and other metabolic therapies can be implemented to help manage cancer (22).  

The Ketogenic Diet.png

In this framework, they propose that metabolic therapies, such as the ketogenic diet, can stress cancer cells which limits their replicative potential.  This is known as the press portion of treatment.  It's this portion that is proposed to make cancer cells more susceptible to conventional treatments such as chemotherapy and radiation therapy which, in their description, would be the pulse portion of treatment (22).  Therefore, the goal is to constantly keep cancer cells under stress and intermittently increase the aggressiveness of treatment which in theory should lead to increased efficacy of treatments.

Take a deep breath, because we're going down a pretty deep pathway again, but we'll sum up and I promise it'll be understandable and relatable in just a minute!

Research continues to uncover ways that the ketogenic diet has effects on genetic, epigenetic, enzymatic, and molecular pathways.  These pathways have been shown to affect cancer in a variety of ways.  

The PI3K/AKT/mTOR pathway is one signaling pathway responsible for controlling the cell cycle.  In a few words, the mTOR pathway is like the gas pedal for cellular growth.  In cancer cells, it has been found that this pathway is upregulated, (basically the pedal is to the metal) leading to uninhibited cellular proliferation (7).  

The ketogenic diet has been shown to downregulate this pathway, essentially taking the foot off the gas, leading to decreased cellular replication (13).  

Something called Insulin-like growth factor 1 (IGF-1) is a signaling molecule that activates the PI3K/AKT/mTOR pathway.  Elevated levels of IGF-1 are also associated with a worse prognosis in patients with cancer.  

The ketogenic diet has been shown to decrease IGF-1 levels (8).  

As previously discussed, as cancer cells grow they experience periods without oxygen.  This upregulates the expression of HIF (hypoxia-inducible factors) which then upregulate the production of VEGF (vascular endothelial growth factor) and this ultimately leads to the growth of new blood vessels.  

To illustrate, It's kind of like when you try to hold your breath underwater.  As soon as you go down, you realize, "hey, I really want to be back above water and breathe like I always do".  That feeling of being starved for oxygen is relatable to those hypoxia-inducible factors...your cells want to 'breathe' as well.  Having them be in a position where they don't feel like they're getting enough oxygen stimulates them to 'ask' for air.  The body responds by upregulating the production of vascular endothelial growth factor, which stimulates vascular growth since blood vessels are how your body delivers oxygen (among other things) to your cells.  

It's a normal response...but one that the body should resist when the cells asking for help are cancer cells.

A ketogenic diet has been found to inhibit both HIF1 and VEGF which in turn prevented new blood vessel formation ultimately decreasing tumor growth (27).

Besides what we've talked about already, ketones have numerous other effects such as being type 1 HDAC (histone deacetylase) inhibitors (25), inhibiting NF-κB (nuclear factor kappa B) (27), and upregulating SIRT1 and AMPK (AMP-activated protein kinase) (15).  We're not going to dive into all the factors and mechanisms for how ketones affect the body and cancer...because people with degrees in molecular biology and biochemistry just aren't that common.  It just needs to be understood that the ketogenic diet has a lot of supported studies done by really smart people to show its benefits go far beyond just limiting glucose availability...as well as far beyond what you end up seeing in the mirror.

What we just talked about:

  • The ketogenic diet has been found to downregulate the PI3K/AKT/mTOR molecular pathway
  • The ketogenic diet has been found to decrease levels of IGF-1
  • The ketogenic diet has been found to inhibit both HIF1 and VEGF
  • The ketogenic diet has a lot of other effects that we just can't talk about in one post, and the number of studies on keto are increasing steadily

What all that means:

  • Again, what all this means is that the ketogenic diet has promising evidence to support normal cells while compromising or slowing tumor cell growth.

 

Human Trials


Much of the researched published on the ketogenic diet has been done in a preclinical setting.  This means that the majority of studies have been performed in cell cultures or animal models, and not on actual people with cancer.  

This isn’t surprising because it's hard to convince a research committee to research a dietary intervention in patients with cancer.  However, there are studies looking at using a ketogenic diet as an adjunct to conventional therapy as well as case reports of the ketogenic diet used as a monotherapy.

Every year more clinical trials are approved that look at the effects that the ketogenic diet has in patients with cancer.  So far clinical studies indicate that a ketogenic diet is beneficial in cancers of the brain, rectum, and lung.  However, pre-clinical data indicates it is beneficial in a host of other cancer types.  

  • Two pediatric patients put on a ketogenic diet had decreased tumor cell glucose uptake (29).  Both patients saw clinical improvements and one experienced a stable remission after 12 months on the diet (29
  • Ten patients with incurable cancer were put on a ketogenic diet.  After 28 days half of the patients had a stable or partial remission (5). 
  • Eleven patients with advanced cancers were put on a ketogenic diet and it was found that after 4 weeks 54.5% of patients had stable or improved disease (24). 
  • Six patients undergoing radiation therapy were put on a ketogenic diet.  Five of the six with early-stage cancer experienced tumor regression (9)
  • A retrospective study looking at 53 patients with glioblastoma multiforme found that a ketogenic diet is safe and well tolerated when undergoing standard of care treatment for GBM (4). 
  • A pilot study looking at the effects of a ketogenic diet on 16 patients with advanced cancer found that the five who stayed on the diet for a 3-month period had an improved quality of life (19)
  • A 65-year-old female with glioblastoma multiforme was placed on a ketogenic diet for 4 weeks.  At four weeks no tumor could be detected on PET or MRI.  Two months after discontinuing the diet she had a recurrence and passed away (28).

 

What's the Takeaway?

The ketogenic diet can be a powerful addition to a treatment plan.  Is it a cure for cancer?  No.  Is it for everyone?  No.  Remember, just like anything else a person with cancer would do as part of their fight against the disease, their doctor, or team of doctors, should be involved and advise on a case by case basis.

I'm not saying that people should go and try out the ketogenic diet just for the heck of it.  What today's blog really aims to show is that the ketogenic diet can be much more than just a passing fling into the dieting world.  There are distinct effects to your body that are happening right now if you've gone keto; and while we all want to see results on a macro-scale, some of the biggest, most profound changes happen in the micro-scale, before you'd ever see it.

The point is if you've been placed on the ketogenic diet by your doctor, oncologist, or care team, don't just think it's about losing pounds.  That's part of it, but just like any treatment plan, the results won't necessarily be overnight.  Don't be discouraged because the before and after pictures haven't come out yet.  The more important before and after might be at the cellular level, and you'll have to ask your doctor...but I'll bet it's looking awesome!

 

Keep posted for Part III in our Ketogenic Blog series, where we'll talk about other benefits and uses for the ketogenic diet that aren't restricted to the realm of cancer, and thank you for reading!

 

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(Our blog isn't designed to provide specific medical advice or replace a medical professional.  We do not recommend starting a new diet plan, such as the ketogenic diet without checking with your physician first.  If you have any specific questions about your health, how to make changes responsibly, or would like to set up an appointment with our clinic, head to our 'Contact Us' page and let us know)! 

 

 

References

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Michael Nelson