Dietary Restrictions Treat Cancer as a Metabolic Disease
Division Of Cancer Treatment And DiagnosisIn an era of targeted cancer treatment strategies, researchers try to exploit the inherent differences between normal and cancer cells. For example, patients often experience significant side effects when cell-killing (cytotoxic) chemotherapy is used because the drugs circulating through the bloodstream affect not only cancer cells but healthy cells as well. Targeted treatments such as Gleevec are designed to interfere primarily with molecules and cells that are actively involved in the cancer process but leave healthy cells alone.
Douglas Robert Spitz, Ph.D., director of the Free Radical Radiation Biology Program at the University of Iowa, thinks he may also be able to direct certain chemotherapies towards cancer cells by changes in the diet. If successful, the new strategy would allow them to deliver larger doses of these drugs more safely.
The body normally converts (metabolizes) food into energy by breaking down the glucose from carbohydrates (glycolysis). However, there is a second way that the body delivers chemical energy – in the form of adenosine triphosphate (ATP) – to its cells. Mitochondria are found in nearly every cell type in the body and because these “cellular power plants” use oxygen to create ATP, the process is known as mitochondrial respiration, Dr. Spitz explained. Researchers have known that cancer cells get their energy by increasing glycolysis, “since their mitochondrial respiration is somewhat compromised,” he added. “So we asked: what if you threaten their glucose energy supply? Will they be able to compensate with mitochondrial respiration?”
In work supported by NCI*, Dr. Spitz and his colleagues are treating human cancer cells with 2-deoxyglucose (2DG), an agent that inhibits both glucose metabolism and also the cells’ ability to cope with damaging oxidizing compounds known as hydroperoxides. They are finding that these glucose-starved cells are more likely to be found and killed by both radiation and chemotherapy. Compared to cells that were not treated with 2DG, both radiation and the chemotherapy drug cisplatin were more effective against human head and neck cancer cells treated with 2DG. The same was true of pancreatic cancer cells targeted with gemcitabine. The researchers will continue to refine this strategy and try to determine how best to increase the oxidative stress put on the cancer cells.
Before they can test the idea in a human trial, they also need to learn more from testing in mouse models, Dr. Spitz said. To reduce glycolysis in animals – and ultimately humans – you have to develop a diet that will safely force the body to switch its metabolism over to mitochondrial respiration. A ketogenic diet does this by essentially starving the body of carbohydrates, he explained. The dietary formulation they are testing in mice has a 10:1 ratio of fat to protein. Early results with mice on a ketogenic diet show that both radiation and cisplatin are significantly more effective at delaying tumor growth and extending survival when combined with 2DG, which can safely be given to humans as well.
“Radiotherapy and certain kinds of drugs like cisplatin kill cancer cells by increasing oxidative stress,” Dr. Spitz added. “When we manipulate these cancer cells closer to the edge of survival, smaller amounts of drugs and radiation appear to have a greater impact.”
NCI Program Director Suzanne Forry-Schaudies, Ph.D., commented, “Inhibiting and/or modifying cancer metabolism is an important and timely area of research. What makes Dr. Spitz’s work unique is the exploration of diet modification in combination with 2-DG, chemotherapy, or radiation treatment. The rational combination of therapeutic agents is currently an area of emphasis in NCI’s Division Treatment and Diagnosis.”
*Grant Number 1R21CA139182-01