The War on Cancer – 05-2015

by Ralph W. Moss, PhD

Cancer and Its Strange Metabolism

One of the key characteristics of cancer is abnormal metabolism.

A normal human cell takes in glucose (i.e., sugar) as its main fuel source and, through a very efficient mechanism, turns each glucose molecule into as many as 36 packets of ATP energy (Rich 2003). This method is called oxidative phosphorylation (OxPhos, for short), which takes place in specialized bodies within each cell called the mitochondria. But cancer cells typically have lost half their mitochondria and, therefore, much of their ability to perform this trick. They must rely on a primitive and relatively inefficient method of energy generation: fermentation. In this method, the cell turns one molecule of glucose into just two packets of ATP energy. A byproduct of fermentation is lactic acid. So, basically, cancer cells ferment, utilizing the same process that turns milk into yogurt, or grape juice into wine.

Through the work of the great German biochemist Otto Warburg, MD, and other scientists, such as Peter Pedersen, PhD, of Johns Hopkins Medical Institution, Baltimore, we now know a great deal about how and why cancer cells rely on fermentation for their energy needs. For instance, a normal cell typically has 200 or so mitochondria. But cancer cells typically have lost half of these, and therefore make up for this mitochondrial deficiency through fermentation. Given the fact that cancers often replicate quickly, their avidity for glucose is a defining characteristic of most tumors.

Proof of this is the accuracy of positron emission tomography (PET) scans. In a PET scan, a patient is injected with a radioactive form of glucose, called FDG. About an hour later, doctors scan the body, looking for signs of radioactivity. Areas of brightness on the scan indicate where glucose in being taken up in greater than normal amounts. Generally speaking, areas that light up coincide with primary tumors or metastatic growths. The more a tumor glows on the PET scan, the more “avid” it is for glucose, and the more malignant it is likely to be. The PET scan thus both utilizes the so-called “Warburg effect,” and is its most dramatic proof of principle.

Since cancer is typically associated with this heightened consumption of glucose (a process that Warburg called “aerobic glycolysis”), there should be a way to decrease its supply of sugar and thereby slow or halt its growth. Over the years, several ways have been suggested. Pharmaceutical companies are also at work on a number of compounds that block the uptake of glucose by tumors. But a simple self-help strategy comes to mind: one could reduce one’s overall intake of food. This is partial or complete fasting. Another more focused method involves the consumption of few carbohydrates, the ultimate source of most of the glucose that circulates in our bloodstream. One can even consume so few carbohydrates that the body then switches to burning fatty acids for energy. This state is called ketosis, and the regimen in question the “ketogenic diet.”

Dietary restriction, intermittent fasting and the ketogenic diet have all been explored as means of controlling the growth of cancer since the 1920s. But since the publication of Prof. Thomas Seyfried’s Cancer As A Metabolic Disease (2012), this method has become increasingly popular among cancer patients. At the same time, it has come under furious attack from some doctors and scientists, on both theoretical and practical grounds. Often these arguments are tinged with intense emotion. People become attached to their own dietary regimens and resent any attempts to change them.

But, emotion aside, the key question is what does the science show on the efficacy of this approach?

In December 2014, the prestigious online journal PLOS One published a systematic review and meta-analysis of the best studies of the past 20 years that have evaluated dietary restriction regimens for cancer such as caloric restriction, the ketogenic diet and intermittent fasting (Lv 2014). The authors come from the University of Nanjing, China. They reviewed a total of 1463 articles and winnowed this down to 157 papers for detailed review. In the end, 59 animal studies fulfilled all of their rigorous inclusion criteria. This selection yields a comprehensive overview of the state of the science. We are thus in a much better position to evaluate the merit of dietary strategies, at least from the point of view of laboratory science.

The authors’ bottom-line conclusion was as follows: “About 90.9% of the relevant studies showed that caloric restriction plays an anti-cancer role”(emphasis added).

The ketogenic diet was also effective. Intermittent fasting was beneficial, but not as significant at preventing cancer as going into ketosis and limiting the number of calories.

The authors conclude: “Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration. More clinical experiments are needed and more suitable patterns for humans should be investigated.”

Caloric Restriction

In 1909, C. Moreschi made the first observation that caloric restricted diets led to a decrease in tumor growth. (All that I could find about Moreschi was that he or she was a colleague of Prof. Paul Ehrlich of the Royal Prussian Institute for Experimental Therapeutics in Frankfurt-am-Main, Germany.) The great Peyton Rous, who later won the Nobel Prize for his work on viruses, pursued the topic at the Rockefeller Institute. Kanematsu Sugiura, DSc, of Sloan-Kettering Institute, New York, experimented with caloric restricted diets in the 1920s. As David Kritchevsky, PhD, of the Wistar Institute, Philadelphia, wrote: “Sugiura and Benedict (1926) found that after excision of spontaneous tumors there was 82 percent recurrence in fully fed mice but only 27 percent recurrence in underfed mice” (2002).

That was a 55% difference in recurrences. Yet this finding also fell by the wayside. Sugiura told me in 1974 that this was because cancer doctors of the time recoiled at the idea of “starving” their patients, due to a fear of initiating or exacerbating cancer cachexia, the wasting syndrome.

Experiments with calorie restriction did not resume until the work of Albert Tannenbaum and Carl A. Baumann in the 1940s and then skipped another few decades. More recently, it has come into vogue, after it was found that “energy restriction enhances DNA repair and moderates oxidative damage to DNA. Energy restriction reduces oncogene expression as well” (Kritchevsky 2001).

In the Nanjing study, the most frequently studied cancer types were mammary (breast), prostate, brain, pancreatic, and hepatic cancers, but skin, colorectal and ovarian cancers were also sometimes investigated. Forty of the forty-four relevant studies (90.9%) “supported the positive anticancer role” of calorie restriction.

It is more than coincidental that many religious and philosophical systems have specified periodic fasts throughout the calendar year. In Judaism, although Yom Kippur is the best known, there are seven fast days in the calendar. One thinks of Lent in the Catholic tradition and Ramadan in Islam. Could it be that these ancient traditions found their way to this concept because of health reasons, as well as religious penance?

Ketogenic Diet

A ketogenic diet is one in which carbohydrates are so restricted that the person fulfills his or her energy requirements through the metabolism of ketone bodies. There is a great deal of mythology surrounding the topic of ketogenesis. The most prevalent confusion, which obscures many discussions of the topic, is a confusion between ketosis and ketoacidosis. The latter is a very dangerous production of huge amounts of highly acidic ketones, generally seen in uncontrolled type 1 diabetics. Ordinary ketosis, such as that attained in a carbohydrate-restricted diet, is a common and normal condition seen during periods of fasting, including sometimes even during one’s normal overnight fast. Since the 1970s, followers of the diet doctor Robert Atkins, MD, have used ketosis as a way to rapidly lose excessive weight.

According to the Chinese authors, there have been nine high-quality studies in mice of ketone-inducing carbohydrate restriction and cancer. The tumor types included primary prostate, brain, colon, and stomach, as well as metastatic cancers.

“Eight of the nine studies (88.9%) supported that carbohydrate restriction is protective [in] cancer,” said the authors of their recent meta-analysis.

The amount of carbohydrates in these experiments ranged from 0% to 20% of the diet. A “nutritionally complete and commercially available ketogenic diet” was also studied, and yielded positive results as well. In humans, a diet of approximately 25 to 30 grams of carbohydrate per day will put one into ketosis.

Intermittent Fasting (IF)

There are eight high-quality studies on intermittent fasting and cancer. Five of these (62.5%) reported positive conclusion. Three studies investigated the role of IF on initiation of cancer, and two of them showed the effectiveness of IF.

Meta-Analysis

The authors also combined the results of 22 studies, 21 of which involved calorie restriction. The pooled effect of calorie restriction was a relative risk of cancer of 0.20. This means that animals that were put on calorie restriction had only one-fifth the incidence of cancer as mice eating as much as they wanted (ad libitum). These results were statistically significant. Here are two of the most dramatic findings.

Von Tungeln Study

. Dr. Linda S. von Tungeln and colleagues at the National Center performed the first study in 1996 for Toxicological Research, Jefferson, Arkansas. The mice in question were given one of two carcinogens.

While between 33% to 50% of the mice on an ordinary ad libitum diet developed liver nodules, including cancers, there were no hepatic nodules in similarly treated mice on a calorie-restricted diet.

Von Tungeln concluded: “Over-nutrition could be an important factor in human diet-related cancer.”

Blando Study

. Another study is from Jorge Blando et al., of the University of Texas M. D. Anderson Cancer Center (2011). Mice that were predisposed to develop prostate cancer were placed on a 30% calorie-restricted diet and then compared to overweight controls and obese animals.

Thirty percent caloric restriction (CR) “significantly reduced the incidence of in situ adenocarcinomas” at 6 months compared to the both the overweight and diet-induced obesity regimen animals. The 30% caloric reduction “significantly delays prostate cancer progression. …”

This paper contains another astonishing finding: “Notably, 30% CR completely suppressed the formation of invasive adenocarcinomas at both 3 and 6 months. …”

That’s right – there was no invasive prostate cancer in the group that had their calories restricted by 30%. But obesity was also associated with a more aggressive tumor: “[A]t 6 months of age, both the overweight control and diet-induced obesity (DIO) groups had poorly differentiated adenocarcinomas, with a significantly greater incidence observed in the DIO diet group compared to the overweight control diet group.”

Lately, there is renewed interest in calorie restricted or ketogenic diets in human cancer, mostly as a result of Pedersen’s work at Hopkins and Seyfried’s outstanding book. There has also been a persistent drumbeat of statements that ketosis is harmful and could even accelerate tumor growth (Bonuccelli 2010). I cannot address these concerns in detail in this article. However, my overall perception is that if it were true that ketosis were harmful in the context of cancer, then one would expect to see that demonstrated in the many high quality studies reviewed in the recent meta-analysis, and especially in the nine papers that specifically evaluated the ketogenic diet. Instead, as shown, eight of those nine ketosis studies supported the idea that carbohydrate restriction was highly protective against cancer. This concept is currently being subjected to clinical trials.

It is even more true today, as it was a decade ago, that “… the use of the ketogenic diet internationally has increased dramatically” (Kossoff 2005)

Overall, the ketogenic diet remains a highly promising strategy for diminishing the growth and aggressiveness of cancer. But, overall, I would say there is very little enthusiasm in our profit-driven medical system for researching simple dietary approaches.

The World Turned Upside Down: A Brief Book Review

I would also call the reader’s attention to a new book available online through print and e-reader called The World Turned Upside Down, by Richard David Feinman, PhD. Feinman is professor cell biology at the SUNY Downstate Medical Center in Brooklyn, where he has been teaching for over 40 years. He is the former coeditor-in-chief of the journal Nutrition and Metabolism and has organized various conferences on the nutritional and metabolic aspects of carbohydrate restriction. He is the author of 77 PubMed-listed publications, dating to 1977. I think it is fair to say that he is a reliable guide to the intricacies of carbohydrate restriction and ketogenesis as it relates to such topics as weight loss, diabetes and cancer. But this is no dry textbook. Feinman intersperses personal anecdotes among his scientific explanations. The result is a highly accessible, thoroughly enjoyable, review of the “second low-carbohydrate revolution.” (The first such revolution was that of Robert C. Atkins, MD at the end of the 20th century.) Carbohydrate restriction on the part of a considerable portion of the population (think of the 86 million Americans with prediabetes alone!) has major implications not just for health and medicine, but for economics as well. It is no exaggeration to call this a “revolution” in thinking and practice.

References

Blando J, Moore T, Hursting S, et al. Dietary energy balance modulates prostate cancer progression in hi-myc mice. Cancer Prev Res (Phila). 2011;4(12):2002–2014.

Bonuccelli G, Tsirigos A, Whitaker-Menezes D, et al. Ketones and lactate “fuel” tumor growth and metastasis. Cell Cycle. 2010;9(17):3506–3514.

Kritchevsky D. Caloric restriction and cancer. J Nutr Sci Vitaminol (Tokyo). 2001 Feb;47(1):13–19.

———. Caloric restriction and experimental carcinogenesis. Hybrid Hybridomics. 2002;21(2):147–151.

Lv M, Zhu X, Wang H, Wang F, Guan W. Roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models: a systematic review and meta-analysis. PLoS ONE. 2014;9(12):e115147.

Kossoff EH, McGrogan JR. Worldwide use of the ketogenic diet. Epilepsia. 2005;46(2):280–289.

Moreschi, C. Beziehungen zwischen Ernahrung und Tumorwachstum. Z fur Immunitatsforsch. 1909;2:651–667.

Rich PR. The molecular machinery of Keilin’s respiratory chain. Biochem Soc Trans. 2003;31:1095–1105.

Sugiura K, Benedict SR. The influence of insufficient diets upon tumor recurrence and growth in rats and mice. J Cancer Res.1926;10:309–314.

Von Tungeln LS, Bucci TJ, Hart RW, Kadlubar FF, Fu PP. Inhibitory effect of caloric restriction on tumorigenicity induced by 4-aminobiphenyl and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in the CD1 newborn mouse bioassay. Cancer Lett. 1996;104(2):133–136.

Ralph W. Moss, PhD, is the author of 12 books on cancer-related topics. The former science writer at Memorial Sloan-Kettering Cancer Center, for 35 years Moss has investigated the validity of many cancer treatments. He currently directs the Moss Reports, a library of reports for patients on over 200 different cancer diagnoses.