Leukemia cells, like most cancers, are addicted to glucose to generate their energy, but new research shows for the first time that these cells also rely on fatty acid metabolism to grow and to evade cell death.
Inhibiting fatty acid oxidation makes leukemia cells vulnerable to drugs that force them to commit suicide, scientists from The University of Texas M. D. Anderson Cancer Center and The University of Texas Medical School at Houston report in the January edition of the Journal of Clinical Investigation.
"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, M.D., Ph.D., professor in M. D. Anderson's Department of Stem Cell Transplantation and Cellular Therapy.
"Cancer metabolism has attracted renewed, cutting-edge research interest," Andreeff said. "Here we have first identified a metabolic target and our first in vivo results are promising, but there is much more work that needs to be done."
Andreeff and co-senior author Heinrich Taegtmeyer, M.D., D.Phil., professor in the University of Texas Medical School Division of Cardiovascular Medicine, are collaborating to develop drugs based on their research results.
"The leukemia cells' appetite for fat seems to be formidable," Taegtmeyer said. "More importantly, fat oxidation seems to promote leukemia cell survival. Conversely, shutting off fat oxidation makes the cells vulnerable to self-destruction. If these initial results hold up, inhibitors of fat oxidation may become a new way to treat leukemia patients."
In normal cells, the processing of fatty acids in the cell's power-generating mitochondria leads to production of ATP, a molecule that serves as the major source of energy for the cell. The researchers showed that fatty acid oxidation in leukemia cell mitochondria drives cellular oxygen consumption and inhibits the activity of proteins that are vital to apoptosis, the programmed death of defective cells that begins in the mitochondria.
For energy generation, leukemia cells rely on glycolysis, the processing of a glucose molecule in the cellular cytoplasm that produces two molecules of ATP and two of pyruvate. Pyruvate, in turn, is converted to energy by the Krebs Cycle, a series of chemical reactions inside the mitochondria.
In a series of lab experiments, the researchers demonstrated that etomoxir, a drug used to treat heart failure, inhibits the growth of leukemia cells in culture in a dose-dependent manner. They also found that etomoxir sensitizes leukemia cells to drugs that cause apoptosis. The fatty acid synthase/lipase inhibitor orlistat also sensitized leukemia cells to programmed cell death.
Etomoxir treats heart failure by switching the heart's energy supply from fatty acids to pyruvate, which is more efficiently converted to energy by the mitochondria.
Mouse model experiments showed that combining etomoxir with the apoptosis-inducing drug ABT-737 or with cytarabine, a frontline drug for acute myeloid leukemia, reduced the leukemia burden and increased median survival time by 33 percent and 67 percent respectively compared to control group mice.
Additionally, etomoxir was found to decrease the number of quiescent leukemia progenitor cells in half of blood samples taken from acute myeloid leukemia patients. These quiescent cells are important, the researchers note, because they are capable of initiating leukemia and are highly resistant to traditional chemotherapy.
"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 first author Ismael Samudio, M.D., a fellow in Stem Cell Transplantation and Cellular Therapy. "For many years it has been apparent that leukemia cells are addicted to glucose for the generation of cellular energy (ATP). 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."
Research was funded by a Young Investigator Award from Leukemia Texas to Samudio, the Paul and Mary Haas Chair in Genetics held by Andreeff and by grants from the National Cancer Institute and the National Heart, Lung and Blood Institute.
Samudio is now associate professor in biochemistry at the Universidad Javeriana in Bogota, Colombia. Co-authors with Andreeff, Taegtmeyer and Samudio are Michael Fiegl, M.D., Borys Korchin, M.D., Ph.D., and Seshargiri Duvvuri of M. D. Anderson's Department of Stem Cell Transplantation and Cellular Therapy; Romain Harmancey, Ph.D. of the University of Texas Medical School Division of Cardiology; Hagop Kantarjian, M.D., and Marina Konopleva, M.D., Ph.D., of M. D. Anderson's Department of Leukemia; and Kumar Kaluarachchi, Ph.D., and William Bornmann, Ph.D., of M. D. Anderson's Department of Experimental Therapeutics.
About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For six of the past eight years, including 2009, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
Scott Merville | EurekAlert!
World’s Largest Study on Allergic Rhinitis Reveals new Risk Genes
17.07.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Plant mothers talk to their embryos via the hormone auxin
17.07.2018 | Institute of Science and Technology Austria
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Information Technology
17.07.2018 | Materials Sciences
17.07.2018 | Power and Electrical Engineering