Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism

Abstract: Cancer cells, relative to normal cells, demonstrate significant alterations in metabolism that are proposed to result in increased steady-state levels of mitochondrial-derived reactive oxygen species (ROS) such as O2•−and H2O2. It has also been proposed that cancer cells increase glucose and hydroperoxide metabolism to compensate for increased levels of ROS. Given this theoretical construct, it is reasonable to propose that forcing cancer cells to use mitochondrial oxidative metabolism by feeding ketogenic diets that are high in fats and low in glucose and other carbohydrates, would selectively cause metabolic oxidative stress in cancer versus normal cells. Increased metabolic oxidative stress in cancer cells would in turn be predicted to selectively sensitize cancer cells to conventional radiation and chemotherapies. This review summarizes the evidence supporting the hypothesis that ketogenic diets may be safely used as an adjuvant therapy to conventional radiation and chemotherapies and discusses the proposed mechanisms by which ketogenic diets may enhance cancer cell therapeutic responses.

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Alex’s Notes: Cancer and ketones are two very hot topics. To get straight to the point, the review at hand does a nice job of providing the theoretical rationale of how a ketogenic diet may be a useful adjunct to cancer treatments and therapy. The fundamental message is that one of the most universal metabolic changes in cancer cells is an increased rate of glucose utilization, and that ketogenic diets that enhance mitochondrial metabolism while limiting glucose consumption could represent a safe, inexpensive, and easily implemented approach to selectively stress cancer cells.

So what is a ketogenic diet? Quite simply, it is a high-fat, very low-carbohydrate, and moderate to low protein diet. For most people that last part about low to moderate protein needs emphasis. Generally, fat intake in grams is about 3-4 times that of carbohydrates and protein combined. A ketogenic diet is not a high-protein diet, and in fact too much protein can easily kick you out of ketosis via its conversion to glucose (gluconeogenesis). If you want to play around with it the numbers, there is a great online keto-calculator you can use for free.

Amusingly, it was around Hippocrates time that ketogenic diets were first recorded as a therapeutic tool for epilepsy, and it wasn’t until the mid-1990s that it came to the frontline as an acceptable treatment option. But ketogenic diets were not restricted to epileptic children. Dr. Atkins readily promoted them for weight-loss, there is currently a growing interest in their role in endurance sport performance, and some evidence suggests they be beneficial in other neurodegenerative diseases included Alzheimer’s and Parkinson’s.

But getting back to cancer, ketogenic diets have been shown to reduce tumor growth and improve survival in animals. Moreover, fasting – which ketosis mimics – has been shown to enhance responsiveness to chemotherapy and slow tumor growth. Compared to normal cells, cancer cells exhibit increased glucose metabolism as well as alterations in mitochondrial oxidative metabolism that are believed to be the result of chronic metabolic oxidative stress, leading to things such as mitochondrial DNA mutations that stem from increased ROS activity within the cancerous cell.

This leads to an odd role of glucose in cancerous cells. Increased glycolysis is an adaptive response to the dysfunctional mitochondria not to generate energy, but to generate the detoxifying compound NADPH through the pentose phosphate pathway. This helps offset the increased ROS production of the mitochondria. Thus, as the authors state,

“Ketogenic diets may act as an adjuvant cancer therapy by two different mechanisms that both increase the oxidative stress inside cancer cells. Lipid metabolism limits the availability of glucose for glycolysis restricting the formation of pyruvate and glucose-6 phosphate which can enter the pentose phosphate pathway forming NADPH necessary for reducing hydroperoxides. Additionally, lipid metabolism forces cells to derive their energy from mitochondrial metabolism. Because cancer cells are believed to have dysfunctional mitochondrial ETCs resulting in increased one electron reductions of O2 leading to ROS production, cancer cells will be predicted to selectively experience oxidative stress, relative to normal cells, when glucose metabolism is restricted in the case of feeding ketogenic diets.”

Clinical trials support the theory thus far. For instance, in Germany there are patients who have failed traditional cancer therapy and are attempting a ketogenic diet. Preliminary reports show those who stuck with it for over 3 months showed improvement via stable physical condition and tumor shrinkage (or slowed growth).

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