Metabolizing fat may protect leukemia cells

Bone marrow aspirate
showing AML

Researchers at MD Anderson Cancer Center in Houston, Texas, have learned that leukemia cells rely on fatty acid metabolism to grow as well as evade apoptosis.
 
“These findings translate to a potentially transformational approach to controlling leukemia and cancer cell metabolism by therapeutically targeting fatty acid oxidation,” said co-senior author Michael Andreeff, MD, PhD.

The team looked at etomoxir, a drug used to treat heart failure by switching the heart’s energy supply from fatty acids to pyruvate, and observed that it stopped leukemia cell growth in cultures as well as sensitizing the cells to drugs that cause apoptosis. Orlistat, a fatty acid synthase/lipase inhibitor, had the same effect.

When etomoxir was combined with the apoptosis-inducing drug, ABT-737, median survival time increased by 33% in a mouse model. When combined with cytarabine, the frontline treatment for acute myeloid leukemia (AML), median survival increased 67% in a mouse model.

Quiescent cells can initiate leukemia and are highly resistant to chemotherapy. However, etomoxir decreased the number of these progenitor cells in half of the blood samples taken from AML patients.

“Our findings suggest that mitochondrial function and resistance to apoptosis in leukemia cells are intimately linked with the entry of fatty acids into mitochondria,” said Ismael Samudio, MD, the first author. “For many years it has been apparent that leukemia cells are addicted to glucose for the generation of cellular energy. Now our results suggest that leukemia cells are addicted to fatty acids for the function of the Krebs cycle and the prevention of cell death.”

Dr Andreeff and co-senior author Heinrich Taegtmeyer, MD, DPhil, are working to develop drugs based on their findings, which are published in the January edition of the Journal of Clinical Investigation.