TY - JOUR
T1 - Assessing metabolic intervention with a glutaminase inhibitor in real-time by hyperpolarized magnetic resonance in acute myeloid leukemia
AU - Zacharias, Niki M.
AU - Baran, Natalia
AU - Shanmugavelandy, Sriram S.
AU - Lee, Jaehyuk
AU - Lujan, Juliana Velez
AU - Dutta, Prasanta
AU - Millward, Steven W.
AU - Cai, Tianyu
AU - Wood, Christopher G.
AU - Piwnica-Worms, David
AU - Konopleva, Marina
AU - Bhattacharya, Pratip K.
N1 - Publisher Copyright:
2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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/NADþ 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.
AB - 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/NADþ 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.
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U2 - 10.1158/1535-7163.MCT-18-0985
DO - 10.1158/1535-7163.MCT-18-0985
M3 - Article
C2 - 31387889
AN - SCOPUS:85074445362
SN - 1535-7163
VL - 18
SP - 1937
EP - 1946
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 11
ER -