The Study

Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States.

Malignant tumor neoplasms require a lot of energy, as they grow quickly. Cachexia is described as a metabolic syndrome that leads to a loss of muscle weight and the depletion of fat deposits. One theory is that the excessive consumption of glucose by a growing tumor leads to a depletion of glucose in the blood and then in later stages of tumor growth, a depletion of glycogen stores in the liver. Glycogen depletion is the followed by muscle degradation and depletion of fat. Hence, the authors state that cachexia syndrome can result in a poor response to chemotherapy, fatigue, and a reduced quality of life for cancer patients.

Approximately 83% of pancreatic cancer patients demonstrate cancer-induced cachexia, which significantly contributes to cancer-related deaths. The authors of this study suggest that the “inhibition of cachexia along with cancer cell growth may be an effective strategy for the management of pancreatic cancer.”

One of the approaches to slow the cancer cachexia may be keto-adaptation, a high fat land low carbohydrates level in a diet (LCHF diet). This diet switches the body to an alternative energy source, namely ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone). It significantly decreases overall blood glucose levels. The need for carbohydrates is reduced without harming normal body tissues. Further, the authors note that a LCHF diet should reduce the availability of glucose for cancer cells and decrease glycolysis in them. Given that most neoplasms are not able to use ketones as an energy source, there are hypotheses where LCHF diet and ketone increase in the blood possibly slows down tumor growth and stops the development of cancer cachexia.

Method

In this study, cancerous cells were implanted in laboratory mice. The animals were subjected to LCHF diet and keto-adaptation. In the blood of the experimental mice, the levels of ketones as an alternative energy source were significantly increased.

Results

According to the results of the experiment ketone bodies diminished tumor growth and damaged cancer cells metabolism. They decreased the level of glycolysis and synthesis enzymes responsible for the key reactions of glucose metabolism in the cell. Moreover, it’s an impressive fact that the increased consumption of ketone bodies caused a significant decrease in the degradation of muscle fibers. In other words, ketogenic diet caused metabolic reprogramming of cancer cells and slowed the development of cachexia in experimental animals.

Conclusion

The authors conclude that the study indicates, “that ketone bodies revert metabolic adaptations in pancreatic cancer cells to induce growth arrest and cell death. Further, the metabolic reprogramming of tumor cells by ketone bodies is responsible for diminishing cancer cell-induced cachexia in cell line models and animal models of pancreatic cancer.

Also, the authors note that Reactive Oxygen Species (ROS), known as free radicals, promotes several inflammatory pathways leading to tumor formation. The study observed a reduction in ROS levels after treatment with ketone bodies. The importance reducing oxidative stress leads to inhibition of histone deacetylas. The authors’ highlight that Inhibition of histone deacetylase activity has been shown to suppress or prevent cancer growth.

The study also observed a reduced expression of glucose transporter GLUT1 and glycolytic enzyme LDHA in pancreatic cancer cells upon treatment with ketone bodies. “Inhibition of GLUT1, which is the main transporter of glucose in cancer cells, is currently being considered for cancer therapy. Also, LDHA inhibition causes reduced cancer cell proliferation.” Also, the study found that ketone bodies diminished c-Myc expression. The authors suggest that c-Myc is considered an attractive therapeutic target due to its role in modulating cell metabolism, tumor initiation, and growth in a variety of cancer types. “Hence, reduced c-Myc expression by ketone bodies might contribute to the growth inhibitory effects of ketone bodies in pancreatic cancer.” Other studies suggest that c-Myc inhibition leads to regression of lung cancer, bladder cancer and pancreatic cancer.

The study indicates, “reduced tumor growth and tumor weight, along with a reduced proliferation of tumor cells in tumor-bearing mice that were subjected to a ketogenic diet relative to regular chow. Overall, along with a reduced tumor burden, the ketogenic diet also improved muscle mass and body weight in tumor-bearing mice. Hence, a ketogenic diet may serve as an anticancer agent as well as an anticachectic agent”.

In conclusion, the authors state that they “have demonstrated anticancerous and anticachectic properties of ketone bodies in cell culture conditions, as well as the effect of a ketogenic diet on tumor burden and cachexia in animal models. Furthermore, our studies establish a ketone body-induced metabolomics reprogramming as the mechanism of action of a ketogenic diet against cancer and cancer induced cachexia.”

Citation

Shukla et al. (2014) Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia. Cancer & Metabolism, 2:18