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Assessment of the Metabolic Profile of Primary Leukemia Cells
Published on: November 21, 2018
Tracer-Based Metabolic NMR-Based Flux Analysis in a Leukaemia Cell Line
John B Carrigan1, Michelle A C Reed1, Christian Ludwig2
1Institute of Cancer and Genomics Sciences University of Birmingham Birmingham B15 2TT UK.
Abstract:
High levels of reactive oxygen species (ROS) have a profound impact on acute myeloid leukaemia cells and can be used to specifically target these cells with novel therapies. We have previously shown how the combination of two redeployed drugs, the contraceptive steroid medroxyprogesterone and the lipid-regulating drug bezafibrate exert anti-leukaemic effects by producing ROS. Here we report a 13C-tracer-based NMR metabolic study to understand how these drugs work in K562 leukaemia cells. Our study shows that [1,2-13C]glucose is incorporated into ribose sugars, indicating activity in oxidative and non-oxidative pentose phosphate pathways alongside lactate production. There is little label incorporation into the tricarboxylic acid cycle from glucose, but much greater incorporation arises from the use of [3-13C]glutamine. The combined medroxyprogesterone and bezafibrate treatment decreases label incorporation from both glucose and glutamine into α-ketoglutarate and increased that for succinate, which is consistent with ROS-mediated conversion of α-ketoglutarate to succinate. Most interestingly, this combined treatment drastically reduced the production of several pyrimidine synthesis intermediates.
Insights
This study reveals how medroxyprogesterone and bezafibrate combat acute myeloid leukemia by generating reactive oxygen species (ROS). The combination therapy impacts key metabolic pathways, including the pentose phosphate pathway and pyrimidine synthesis, offering new therapeutic insights.
Area of Science:
- Biochemistry
- Metabolic pathways
- Cancer research
Background:
- High reactive oxygen species (ROS) levels target acute myeloid leukemia (AML) cells.
- Medroxyprogesterone and bezafibrate combination therapy shows anti-leukemic effects via ROS production.
Purpose of the Study:
- To elucidate the metabolic mechanisms of combined medroxyprogesterone and bezafibrate treatment in K562 leukemia cells.
- To understand drug interactions within cellular metabolic networks using 13C-tracer Nuclear Magnetic Resonance (NMR) spectroscopy.
Main Methods:
- Utilized 13C-tracer-based NMR spectroscopy.
- Analyzed metabolic flux from [1,2-13C]glucose and [3-13C]glutamine in K562 cells.
- Quantified changes in metabolic intermediates and pathways under drug treatment.
Main Results:
- Observed pentose phosphate pathway activity and lactate production from glucose.
- Found significant glutamine contribution to the tricarboxylic acid cycle.
- Demonstrated drug-induced decrease in 13C incorporation into alpha-ketoglutarate and increase into succinate, indicating ROS-mediated alpha-ketoglutarate to succinate conversion.
- Reported a drastic reduction in pyrimidine synthesis intermediates production.
Conclusions:
- Combined medroxyprogesterone and bezafibrate therapy alters key metabolic pathways in leukemia cells.
- The observed metabolic shifts, particularly the alpha-ketoglutarate to succinate conversion, are consistent with ROS-mediated effects.
- The significant impact on pyrimidine synthesis suggests a novel therapeutic strategy targeting leukemia cell metabolism.
