Assessing Metabolic Intervention with a Glutaminase Inhibitor in Real-Time by Hyperpolarized Magnetic Resonance in Acute Myeloid Leukemia

Molecular Cancer Therapeutics
Niki Marie ZachariasPratip K Bhattacharya

Abstract

Acute myeloid leukemia (AML) is an aggressive hematopoietic disease characterized by glutamine-dependent metabolism. A novel glutaminase (GLS) inhibitor, CB-839, is currently under evaluation for treatment of hematopoietic malignancies and solid tumors. Our purpose was to measure cellular changes in AML associated with CB-839 treatment and to test the ability of hyperpolarized pyruvate for interrogating these changes to OCI-AML3 cells. Our results show that treatment with CB-839 interfered with the citric acid cycle, reduced the NADH/NAD+ ratio and ATP levels, reduced cell proliferation and viability, and reduced the basal and maximal respiratory capacities [oxygen consumption rate (OCR)]. We observed a reduction of the conversion of hyperpolarized pyruvate to lactate in cell lines and in a mouse AML model after CB-839 treatment. Our in vitro and in vivo results support the hypothesis that, in AML, glutamine is utilized to generate reducing equivalents (NADH, FADH2) through the citric acid cycle and that reduction in redox state by GLS inhibition decreases the rate of pyruvate to lactate conversion catalyzed by lactate dehydrogenase. We propose hyperpolarized pyruvate/lactate measurement as a method for direct monitoring of met...Continue Reading

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Citations

Aug 26, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yi RaoDavid Piwnica-Worms
Jun 6, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Nicholas R PerkonsTerence P F Gade
Nov 5, 2020·Archives of Biochemistry and Biophysics·Tao YuXiongbin Lu
May 23, 2021·The Journal of Biological Chemistry·Yi RaoDavid Piwnica-Worms
Dec 24, 2020·Blood Reviews·Binyan XuYuhua Li

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