Tweaking diets by restricting calories, nutrients, or the time spent eating may inhibit tumor growth and progression, a new study by Semmelweis University, Budapest concludes. The researchers have looked at how popular diets influence cancer development based on the tumor’s metabolic vulnerabilities. Dietary interventions open up new possibilities in cancer therapy, but low patient compliance and not enough clinical trials pose a challenge.

The researchers summarized the result of over 300 studies; both pre-clinical (animal, in vitro) and clinical human trials with a focus on diets that restrict calories and glucose including ketogenic, time-restricted eating, intermittent fasting and fasting-mimicking diets as restricting specific nutrients or the overall calorie content can have an anti-tumorigenic effect.

Cancers are very heterogenous in their metabolic dependencies: there is no one-size-fits all

, says Otilia Menyhárt, senior lecturer at the Department of Bioinformatics, Semmelweis University, first author of the study. “What they do have in common is an extremely high energy need to support their growth”, she adds. Their preferred source of fuel, however, varies. Many cancers, for example, colorectal, cervical, and certain types of breast tumors rely on glucose.

Fructose is an alternative energy source that enhances the growth of prostate cancer cells.

Glutamine, the most abundant amino acid in the blood and the muscles, is the second most frequent growth-supporting substrate after glucose that cancers, including non-small cell lung cancer, pancreatic cancer, myeloma and brain tumors highly depend on.

„When we cut back on the body’s energy source(s)/deprive the body of glucose for a long enough period, the body goes into a fasting state”, Menyhárt explains. After 36-72 hours, the glycogen stores of the liver (and muscles) are emptied and ketone bodies are produced that serve as an alternative fuel. Healthy cells can utilize ketone as fuel. Metabolically inflexible cancers cells cannot adapt to the change as well therefore their ability to get energy from ketones is limited.

Fasting also forces healthy cells to switch from growth to a phase of maintenance and repair, which protects them from toxic insults such as chemotherapy and radiotherapy.

Fast-proliferating tumor cells cannot switch to repair mode. Moreover, the starving tumor cells produce an increased amount of reactive oxygen species, making them more susceptible to treatment-induced DNA damage. That is why fasting prior to and after chemotherapy improves the treatment’s efficiency while also considerably reducing its side effects. Depending on the clinical trial, fasting periods may vary from 24-48 hours to up to five days.

It sounds counterintuitive but a fasted body responds much better to chemotherapy (and radiotherapy)

, Menyhárt says.

“Ketogenic diet in anticancer therapy can lead to increased survival and decreased tumor growth but in certain cancers it accelerates disease progression”, the expert notes. Diets that restrict calories or the eating window, including intermittent fasting (IM), time-restricted feeding or fast-mimicking diets, can be more suitable for those who cannot follow ketogenic diet due to its side effects (fatigue, constipation). These also benefit from the mechanism described above but have a somewhat milder approach which enforces compliance.

Low compliance at clinical trials – either due to the adverse side effects of these diets (e.g. muscle loss) or poor adherence to them –  is one reason why there are not clinical recommendations at this point.

Despite promising results, much of the knowledge on dietary restrictions comes from in vitro and animal studies, which may not accurately reflect real-life situations

, Menyhárt notes. “To change that, protocols that patients are able and willing to follow should be created and clinically tested”, the researcher adds.

As of September, 2023, 35 recruiting or soon-to-be-active interventional clinical trials incorporate caloric restrictions in therapies for glucose-dependent cancers, the study highlights. Most of these clinical trials (12 studies) focus on various molecular types and stages of female breast cancers.

Excess body weight is linked to an increased risk of cancer in at least 13 anatomic sites. The cancer burden attributed to obesity can be as high as 11.9% for men and 13.1% in women. Higher body fat percentage during childhood and adolescence is correlated with an increased risk of malignancy at an older age. Inflammation weakens the immune system and immune cells that cannot fight tumor as effectively, which can increase the risk of developing cancer. 

“The key take-away of the study is that if we want to do ourselves a service, we should cut back on our calories”, Menyhárt notes.

Restricting caloric intake by about a third can drastically reduce inflammation, the risk of cardiovascular diseases, metabolic syndrome and thus the chance of developing cancer by up to 50%

, she adds.

Photo: Bálint Barta – Semmelweis University, illustration: iStock