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Acute myeloid leukemia sensitivity to metabolic inhibitors: glycolysis showed to be a better therapeutic target

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Abstract

Cancer cells alter their metabolism by switching from glycolysis to oxidative phosphorylation (OXPHOS), regardless of oxygen availability. Metabolism may be a molecular target in acute myeloid leukemia (AML), where mutations in metabolic genes have been described. This study evaluated glycolysis and OXPHOS as therapeutic targets. The sensitivity to 2-deoxy-d-glucose (2-DG; glycolysis inhibitor) and oligomycin (OXPHOS inhibitor) was tested in six AML cell lines (HEL, HL-60, K-562, KG-1, NB-4, THP-1). These cells were characterized for IDH1/2 exon 4 mutations, reactive oxygen species, and mitochondrial membrane potential. Metabolic activity was assessed by resazurin assay, whereas cell death and cell cycle were assessed by flow cytometry. Glucose uptake and metabolism-related gene expression were analyzed by 18F-FDG and RT-PCR/qPCR, respectively. No IDH1/2 exon 4 mutations were detected. HEL cells had the highest 18F-FDG uptake and peroxides/superoxide anion levels, whereas THP-1 showed the lowest. 2-DG reduced metabolic activity in all cell lines with HEL, KG-1, and NB-4 being the most sensitive cells. Oligomycin decreased metabolic activity in a cell line-dependent manner, the THP-1 resistant and HL-60 being the most sensitive. Both inhibitors induced apoptosis and cell cycle arrest in a cell line- and compound-dependent manner. 2-DG decreased 18F-FDG uptake in HEL, HL-60, KG-1, and NB-4, while oligomycin increased the uptake in K-562. Metabolism gene expression had different responses to treatments. In conclusion, HEL and KG-1 show to be more glycolytic, whereas HL-60 was more OXPHOS dependent. Results suggest that AML cells reprogram their metabolism to overcome OXPHOS inhibition suggesting that glycolysis may be a better therapeutic target.

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The data used and/or analyzed during the current study are available by contacting the corresponding author with reasonable request.

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Acknowledgements

The present work was supported by Center of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Portugal and by National Funds via Foundation for Science and Technology (FCT) through the Strategic Project UID/NEU/04539/2019, COMPETE-FEDER (POCI-01-0145-FEDER-007440), UIDB/04539/2020, and UIDP/04539/2020 (CIBB). RA was supported by FCT trough a PhD Grant (SFRH/BD/51994/2012).

Funding

The present work was supported by the Center of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, Portugal and by National Funds via Foundation for Science and Technology (FCT) through the Strategic Project UID/NEU/04539/2019, COMPETE-FEDER (POCI-01-0145-FEDER-007440), UIDB/04539/2020, and UIDP/04539/2020 (CIBB). RA was supported by the Portuguese Foundation to Science and Technology (FCT) through a PhD Grant (SFRH/BD/51994/2012).

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Authors and Affiliations

  1. Faculty of Medicine (FMUC), Laboratory of Oncobiology and Hematology (LOH) and University Clinic of Hematology, University of Coimbra, Azinhaga de Santa Comba-Celas, 3000-548, Coimbra, Portugal

    Beatriz Lapa, Ana Cristina Gonçalves, Joana Jorge, Raquel Alves & Ana Bela Sarmento-Ribeiro

  2. Coimbra Institute for Clinical and Biomedical Research (iCBR) - Research Area of Environment Genetics and Oncobiology (CIMAGO), FMUC, University of Coimbra, Coimbra, Portugal

    Beatriz Lapa, Ana Cristina Gonçalves, Joana Jorge, Raquel Alves, Ana Salomé Pires, Ana Margarida Abrantes, Margarida Coucelo, Maria Filomena Botelho, José Manuel Nascimento-Costa & Ana Bela Sarmento-Ribeiro

  3. Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal

    Ana Cristina Gonçalves, Joana Jorge, Raquel Alves, Ana Salomé Pires, Ana Margarida Abrantes, Margarida Coucelo, Maria Filomena Botelho, José Manuel Nascimento-Costa & Ana Bela Sarmento-Ribeiro

  4. Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal

    Ana Cristina Gonçalves, Joana Jorge, Raquel Alves, Ana Salomé Pires, Ana Margarida Abrantes, Margarida Coucelo, Maria Filomena Botelho, José Manuel Nascimento-Costa & Ana Bela Sarmento-Ribeiro

  5. Faculty of Medicine (FMUC), Biophysics Unit, University of Coimbra, Coimbra, Portugal

    Ana Salomé Pires, Ana Margarida Abrantes & Maria Filomena Botelho

  6. Clinical Hematology Department, Centro Hospitalar Universitário de Coimbra (CHUC), Coimbra, Portugal

    Margarida Coucelo & Ana Bela Sarmento-Ribeiro

  7. Institute of Nuclear Sciences Applied to Health (ICNAS), University of Coimbra, Coimbra, Portugal

    Antero Abrunhosa

  8. Faculty of Medicine (FMUC), University Clinic of Oncology, University of Coimbra, Coimbra, Portugal

    José Manuel Nascimento-Costa

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  1. Beatriz Lapa
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Contributions

ACG and ABSR designed the experiments. BL and ACG drafted the manuscript. BL, ACG, RA, JJ, ASP, AMA, AA, MFB, and MC performed or interpreted the experiments. BL, JJ, and RA executed the statistical analyses. JMNC and ABSR revised the manuscript.

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Correspondence to Ana Cristina Gonçalves.

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This research project was approved by the Institutional Review Board of the Medical School of the University of Coimbra (reference: 072-CE-2017).

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Lapa, B., Gonçalves, A.C., Jorge, J. et al. Acute myeloid leukemia sensitivity to metabolic inhibitors: glycolysis showed to be a better therapeutic target. Med Oncol 37, 72 (2020). https://doi.org/10.1007/s12032-020-01394-6

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