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Do Ketones Fuel Cancer? The Low-Carb Experts Respond

Posted Mar 02 2011 2:14pm

It’s time to bat around another reader-inspired question about an important subject within the realm of health that virtually everyone reading this right now has had to deal with in their lifetime through a diagnosis of a family member or friend–that would be CANCER. Researchers have been looking at what the possible culprits in what is causing this terrible disease for decades, but unfortunately most of the studies have been geared towards finding a pharmaceutical answer. Oftentimes, the natural nutritional remedies aren’t even investigated because there is no money to be made promoting that to cancer victims. It’s just such a shame that finding a cure for cancer seems to be predicated on how much money can be made treating people that have it. If I’m wrong about this, then somebody tell me otherwise. I guess I’ve just become so jaded by how health is viewed from the very medical professionals who purport to be about improving health.

One of the most exciting areas of research that is taking place right now is how a ketogenic, low-carb diet could be used as a therapeutic tool for treating people afflicted with cancer when chemotherapy and other procedures have proven ineffective. Thanks to the great work of people like Dr. Eugene Fine and Dr. Thomas Seyfried who are testing this theory about how ketones can help shrink the size of cancerous tumors and quite possibly be used as a preventative measure for people concerned with getting cancer. The funding for these kind of studies has been paltry compared with the drug research, but the outlook for the ketogenic approach looks quite promising.

Enter the following monkey wrench one of my readers shared with me recently regarding this study published in the September 21, 2010 issue of the scientific journal Cell Cycle claiming that ketone bodies can INCREASE tumor growth by as much as two-and-a-half times reflecting a “Reverse Warburg Effect.” Personally, I’d never heard of anything like this, especially in light of the work of Fine and Seyfried on the BENEFITS of ketones in REDUCING cancer cell growth as part of their studies. Here’s what my reader wrote to me in an e-mail:

I am a long-term lowcarber (very high-fat — all manner of fat from grass-fed animals, eggs, nuts etc.) and am often in ketosis — more often than not. I love livin’ la vida low-carb and find it the easiest way to avoid the type 2 diabetes and obesity that has plagued so many members of my family. However, today someone posted some disturbing information on another low-carb diet forum regarding recent studies like this one claiming to show that ketones fuel cancer. Do you have any thoughts on this?

Since this was such a foreign concept to me based on all that I know about how low-carb ketogenic diets respond to cancer in just the opposite manner (see here , here , and here for just a few examples), I couldn’t help but ask some of my expert friends in the low-carb community to respond. Here’s what they had to say:

GARY TAUBES , author of Why We Get Fat

I read this paper and the whole thing is very weird. I also recently reported, as I probably told you, an article on the diabetes cancer link and virtually everyone in the field thinks it’s insulin and IGF that drive growth and explain the association between cancer and diabetes.

In fact, metabolic syndrome and obesity are also associated with greater risk of cancers and in those cases there would certainly not be increased ketone production (insulin suppresses ketone production). So all these would point to insulin and maybe IGF and not ketones, which is what they imply.

Finally, and I may be wrong, only in uncontrolled diabetes would ketone production be high, and certainly not in Type 2 diabetes. Then there’s all the evidence that isolated populations eating their traditional diets got relatively little to no cancer. I discuss this in GCBC. This includes populations that ate no carbohydrates (the Inuit, the Masai, etc.). So that would argue for glucose and insulin related drivers, not ketones.

Still, it’s conceivable, I guess, that if we get cancer and then go on a high-fat, low-carb diet that could make it worse, although that’s easily testable. In fact, there are studies ongoing now, as you know, using ketogenic diets to treat cancers. If it turns out they do nothing or accelerate the cancer growth then that would be a bad sign.

FRED & ALICE OTTOBONI , author of The Modern Nutritional Diseases

The proposition that ketone bodies and lactate (lactic acid) fuel cancer growth is a fascinating thought, but not one that should be of concern to anyone following a low-carb diet. We, too, have not come across such a claim before this. Incidentally, anyone interested cancer development and metabolism should obtain a copy of Cancer Nutrition and Survival by Drs. Steve Hickey and Hilary Roberts (wife). It is an absolute “must.”

About the paper claiming that ketone bodies and lactate (lactic acid) fuel cancer growth, here are our thoughts:

First, as a practical matter (from a nutritional viewpoint), the claim is not biochemically logical.

Second, the study on which it is based is an in-vitro experiment and not necessarily of significance for an intact organism.

We have obtained a copy of the complete paper because the abstract contained statements that are biochemically inaccurate.

First, the biochemical logic: Cancer cells require glucose as their source of energy. As far as is known, glucose is their only energy source. Cancer cells cannot survive, grow, and metastasize without energy.

People on a low-carb diet have no excess glucose (blood or dietary) with which to feed cancer cells. Instead they preserve glucose for its vital role as a blood component by catabolizing fats (and producing a variety of ketones) to provide the energy otherwise supplied by glucose.

Ketone bodies produced in humans as a result of β-oxidation of fatty acids (see Figure 5-2 and pp. 114ff of The Modern Nutritional Diseases) have been shown to be an excellent source of energy for all normal tissues and organs, except the liver. We are not aware that the metabolism of ketone bodies in cancer cells has been elucidated. Thus, there appears to be no biochemical evidence that cancer cells can use ketone bodies as sources of energy.

On the other hand, cancer cells produce lactate (lactic acid) as an end-product of anaerobic metabolism of glucose. Cancer cells use glucose aerobically (to CO2 and H2O) when they are well oxygenated and anaerobically (to pyruvate) when starved for oxygen. Cancer cells, like any normal cells that must survive when oxygen becomes limited, can function either anaerobically or aerobically.

This is possible because energy production in all mammalian cells has two parts, the first half is anaerobic and the second half aerobic. All macronutrients (carbohydrate, fats, and protein) are metabolized anaerobically to pyruvate and/or acetyl CoA (see Figure 4-1, MND). Aerobic energy production begins with the entry of acetyl CoA into the Krebs cycle, which completes the oxidation of acetyl CoA to CO2 and H2O. Some normal cells can operate anaerobically for short periods of time.

The appropriate human cell model for this dual metabolic function is the muscle cell. During normal activity, well-oxygenated muscle cells obtain energy from glucose anaerobically by glycolysis to pyruvate and acetyl CoA followed aerobically by the Krebs cycle. But during heavy exertion, delivery of oxygen to the muscles becomes inadequate with the result that sufficient energy can only be obtained anaerobically by glycolysis of glucose. Glycolysis would stop if the muscle cells did not have an electron acceptor other than oxygen available to them. They keep glycolysis (and energy production) going by using pyruvate as the electron acceptor and reducing it to lactic acid. Lactic acid accumulates in the muscles until adequate oxygen becomes available to oxidize it back to pyruvate and then through the Krebs cycle.

Cancer cells operate in the same manner as muscle cells with the exception that they excrete the lactic acid that is produced. The possibility exists that some lactic acid could be converted back to glucose but, because it is readily excreted, this would be a negligible source of energy.

DR. THOMAS SEYFRIED , Boston College cancer researcher

I know about this study. The study has serious problems. I wrote a letter to the editor of the journal regarding the flaws in the study. I discussed these flaws with Dr. Richard Veech at the NIH, who concurred with my concerns.

Unfortunately, these types of studies will occasionally appear in the literature mainly because the reviews, who know about molecular biology, are unfamiliar with the old literature on energy metabolism.

Here’s Dr. Seyfried’s letter that never got published in the journal:

October 20, 2010
Dr. M.V. Blagosklonny

Editor-in-Chief, Cell Cycle
Roswell Park Cancer Institute

Buffalo, NY

Dear Dr. Blagosklonny,

I am writing in reference to an article that appeared in the September 1 issue of Cell Cycle by Bonuccelli, et al., entitled: “Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism”.

The authors have made serious errors in their data interpretation and the conclusions of their article. There is no evidence in the biochemical literature that ketone bodies can be made from pyruvate in fibroblasts. It is common knowledge in biochemistry that ketone bodies are derived from fatty acid beta-oxidation in liver mitochondria. This information is also presented in the cited articles from Veech and co-workers.

The authors present evidence showing that the ketone body 3-hydroxy-butyrate does not enhance lung metastasis (Fig. 4A), yet the paper title indicates that ketones fuel tumor growth and metastasis. The paper title and abstract are therefore misleading.

Furthermore, no evidence was presented in the paper showing that the MDA-MB-231 cells can survive using only L-lactate or ketone bodies as metabolic fuels. While the authors recommend that it may be unwise to use lactate-containing i.v. solutions in cancer patients, the authors should also recognize that lactate is metabolized to glucose in the liver through the Cori cycle. It is well documented that glucose can stimulate tumor growth. No information was provided on food intake or body weights of the treated and control mice. No information was presented on blood glucose or ketone levels in the tumor bearing mice used in the study. It is difficult to assess the effects of drug injections without this information. Finally, no evidence was presented showing that OxPhos is operational in the MDA-MB-231 tumor cells. Gene expression profiles do not provide the required biochemical and physiological evidence for establishing operational OxPhos in tumor cells.

Unfortunately, the author’s provide misinformation. Such information will cause confusion in the field. I am surprised that the reviewers of this paper did not mention these issues in their critique, as some of the evidence and statements presented contradict basic principles of biochemistry as specified in any general textbook on the subject. If further evidence is needed to support my concerns, I would suggest contacting Drs. Richard Veech, Theodore B. VanItallie and Jong Rho.

Thomas N. Seyfried, Ph.D.

DR. STEPHEN PHINNEY , low-carb researcher and co-author of The New Atkins For A New You

This is an interesting study, not so much because of what they claimed to find, but because of how much they had to ignore to draw the conclusions that they did. I could write a whole book chapter to explain this one study — not just why their conclusions are flawed, but also about the socio-political environment within the science establishment that promotes the publication of what I can only characterized as ‘reductionist garbage’.

But uncharacteristically, I offer you these few relatively brief points.

• some of the last Aboriginal nomads who lived by hunting/herding while in contact with modern medicine (such as the Masai and the Inuit) rarely were diagnosed with (or died of) cancer.

• Injecting a big dose of ketones into the abdomen of a mouse once per day is very different from the hormone and metabolic conditions that induce the body to make its own supply of ketones. To assert that the two are metabolically identical is at least intellectually weak, if not duplicitous.

• All that we are told about the diet of these mice is that they were given ad libitum access to ‘chow’. So what happens if ‘Mickey’ in cage #2 just ate a belly full of this yummy stuff (which is typically more than 60% carbs) and someone then picked him up and jabbed a needle into him delivering a bolus of ketones. Normally, we make ketones when dietary carbs are limited, but in this case these ‘scientists’ are jamming in ketones when the mice still have plenty of carbs. Since the normal (non-cancer) cells in the body love to burn ketones, want to guess what happens to blood glucose after the ketone injection. Of course, blood glucose goes up. Look through their paper as much as you want — they don’t tell you anything about blood glucose after the ketone (or lactate) injections. If blood glucose went up after ketone and lactate injections (just an educated guess), what caused their tumors to grow? Sugar or ketones?

• Multiple studies published in the last 5 years report that a well-formulated ketogenic diet in humans causes a significant reduction in biomarkers of inflammation. In addition to being closely associated with the risk of heart attack and Alzheimer’s disease, inflammation is now known to be positively correlated with many common cancers (including colon and breast cancer). Simply put, if a low carb diet reduces inflammation and a low level of inflammation correlates with less cancer, how did these guys get this paper published without a more rigorous peer review?

Answer. Because the peer review process is confidential, we’ll never know. But as an educated guess, it is much easier to get a paper published that bashes ketones/low carb than a paper that concludes that nutritional ketosis might be beneficial.

You do the math.

DR. ERIC WESTMAN , low-carb researcher and co-author of The New Atkins For A New You

I read two articles from this group. This is a theory with in-vitro studies so it is VERY preliminary in terms of generalizability to intact human organisms. Keep in mind that “cancer” is very complicated!

KAREN RYSAVY , long-time low-carber at “Truly Low Carb”

I have heard lots of evidence to the CONTRARY; this is the very first time I have ever heard anyone suppose that ketosis encourages cancer cells. Based on my research to date, which does not yet include the link you sent, if I were diagnosed with cancer the very first thing I would do is make sure I was in ketosis, then try to stay there for the duration. It would have to be a very compelling “single” study to sway me from this belief.

DR. MARY VERNON , low-carb practitioner in Lawrence, Kansas

This is an interesting article but I can’t extrapolate from it to humans. A PubMed search brings up pages of citations with conflicting conclusions.

However, here is my standard common sense approach to this type of thing:

1) Habeas Corpus-where are all the bodies? Enough people eat this way that if this really generated cancer then you’d think we’d be seeing the uptick in numbers.

2) Prevention and cure may not require the same intervention. The end stages of cancer have a lot more hormonal signals than just the ketones-those hormonal signals, many of which are made by the tumors-may change the way fuel is used.

3) What’s the data? There have been actual studies suggesting the opposite effect than this in prostaste cancer and case reports of beneficial effect in brain cancer for ketogenic diets. We need more info-and the NIH needs to fund studies that have as investigators practitioners who really know how to use this tool-not folks who have read an article or two.

Dr. EUGENE FINE , cancer researcher at Albert Einstein College of Medicine

I haven’t read the Lesanti article in any detail yet, but I see he is studying only one cancer type. Some cancers may indeed depend on ketone bodies. Our hypothesis, in fact states that some cancers may be adapted to the effects of carb
restriction, including ketosis (i.e. may continue to grow), and others may be vulnerable to ketosis. I do have evidence that many cancers are inhibited by ketone bodies.

Summary: Cancers aren’t simple and generalizations are usually wrong.

So, that’s what the experts say in response to this idea that ketones that are produced while on a low-carb diet actually “fuel” cancer cell growth. But what do YOU think? Is it possible for cancerous tumors to grow in the presence of ketone bodies based on all that you know about the role low-carb diets play in this? If sugar feeds cancer (and it does!), then how can the absence of sugar in the blood which occurs when carbohydrates are restricted lead to higher rates of cancer? Is it even fathomable? Let the discussion begin.

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