In mice, a ketogenic diet remodeled the translatome of pancreatic cancer cells, rendering them vulnerable to targeted therapy.
Pill containers often include warnings about specific foods or beverages that should be avoided when taking certain medications. For example, grapefruit juice interferes with the breakdown of statins in the intestines, causing the drug to remain active in the body for too long.1 Similarly, consuming alcohol with medications can be dangerous as it may alter the liver’s metabolism of the drug, leading to added or exaggerated side effects and possible liver damage from overtaxing the body’s overall metabolic funtioning.2
However, not all diet-drug interactions are bad. In a recent study, Davide Ruggero, a cancer biologist at the University of California, San Francisco, and his team found that a high-fat and low-carbohydrate diet—known as a ketogenic, or keto, diet—could remodel the translatome, or the collection of molecules that are actively being translated, of fat-loving pancreatic cancer cells in mice. These modifications enhanced the effectiveness of a targeted cancer therapy in suppressing tumor growth. The findings, published in Nature, lay the groundwork for researchers to investigate personalized drug-diet combinations as potential cancer therapies.3
“We are living in a moment where these different diets—intermittent fasting, ketogenic diet, calorie restriction—are used now more and more for metabolic diseases like diabetes, but there’s been a lot of emphasis on using these diets when thinking about cancer patients,” said Ruggero.
Previously, Ruggero found that mice that were fasting or on a ketogenic diet exhibited increased phosphorylation of a protein called eukaryotic translation initiation factor (eIF4E), which helped the liver metabolize lipids.4 In their recent study, the team wanted to uncover the metabolic mechanisms underlying this beneficial effect and explore how the ketogenesis pathway could be utilized to boost cancer treatment.
First, the team characterized the relationship between high fats and eIF4E by measuring their activity in the liver. Their experiments showed that a ketogenic diet increases fatty acids in the liver, initiating ketogenesis by activating a pathway that begins with phosphorylation of eIF4E. Increased phosphorylation of eIF4E shifted translational control in liver cells, increasing the expression of genes involved in fat metabolism. This triggered a metabolic shift to burning fat for energy instead of the typical glucose. The burning of fat, in turn, produced ketone bodies in the animals’ blood, characteristic of a ketogenic diet.
It was already known that pancreatic cancer, one of the deadliest cancers, can use ketone bodies for an energy source, as an alternative to the typical glucose.3,5 So, Ruggero and his team wondered if they could make pancreatic cancer cells dependent on this eIF4E-initiated pathway for energy by simply modifying the animals' diet.
Ruggero's team utilized a mouse model of pancreatic cancer to test the effects of tomivosertib, a drug that inhibits phosphorylated eIF4E, in combination with a ketogenic diet. With their only food source pharmacologically cut off, the cancer cells starved and tumor growth was blocked. However, the compound had no effect on mice that received a normal diet.
“It was an amazing result,” said Ruggero. “Cancer is not made of cells coming from the universe or Mars or whatever, it is a process that, in fact, hijacks something that was already happening [in our bodies] for other reasons.”
“The buzzword now is ‘diet-drug interactions’,” said Michael Pollak, an oncologist and researcher at McGill University who wasn’t involved in the study. “If we had a cancer-curing diet, make no mistake, that would be my first choice,” said Pollak. Unfortunately, Pollak noted, that isn’t where the scientific evidence is pointing. He explained, “Diet modifications by themselves may not be impactful enough to make a difference, but they may actually sensitize tumors to certain drugs.”
Preclinical cancer studies in mice have shown some promise for keto diets.6 However, human trials in this area have been difficult to interpret, in part because the methods vary widely, and the ideal combinations of foods for different cancer types are not yet known, preventing the field from making strong conclusions.7-9
Read more:
https://www.the-scientist.com/a-keto-diet-could-enhance-cancer-drug-effectiveness-72375
