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

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 metabolic changes occurring in AML patients receiving CB-839. With further optimization, this method may provide a noninvasive imaging tool to assess the early efficacy of therapeutic intervention with GLS inhibitors.

• Authors: Niki M Zacharias, Natalia Baran, Sriram S Shanmugavelandy, Jaehyuk Lee, Juliana Velez Lujan, Prasanta Dutta, Steven W Millward, Tianyu Cai, Christopher G Wood, David Piwnica-Worms, Marina Konopleva, Pratip K Bhattacharya
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 18 Issue 11 Pg. 1937-1946 (11 2019) ISSN: 1538-8514 [Electronic] United States
• PMID: 31387889 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Benzeneacetamides
• CB-839
• Thiadiazoles
• Lactic Acid
• Pyruvic Acid

Topics

• Animals
• Benzeneacetamides (administration & dosage, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• HL-60 Cells
• Humans
• Lactic Acid (metabolism)
• Leukemia, Myeloid, Acute (diagnostic imaging, drug therapy, metabolism)
• Magnetic Resonance Spectroscopy
• Male
• Mice
• Pyruvic Acid (metabolism)
• Thiadiazoles (administration & dosage, pharmacology)
• Treatment Outcome
• Xenograft Model Antitumor Assays