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Acute myeloid leukemia sensitivity to metabolic inhibitors: glycolysis showed to be a better therapeutic target.
Lapa, Beatriz; Gonçalves, Ana Cristina; Jorge, Joana; Alves, Raquel; Pires, Ana Salomé; Abrantes, Ana Margarida; Coucelo, Margarida; Abrunhosa, Antero; Botelho, Maria Filomena; Nascimento-Costa, José Manuel; Sarmento-Ribeiro, Ana Bela.
Afiliación
  • Lapa B; 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.
  • Gonçalves AC; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Research Area of Environment Genetics and Oncobiology (CIMAGO), FMUC, University of Coimbra, Coimbra, Portugal.
  • Jorge J; 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. acgoncalves@fmed.uc.pt.
  • Alves R; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Research Area of Environment Genetics and Oncobiology (CIMAGO), FMUC, University of Coimbra, Coimbra, Portugal. acgoncalves@fmed.uc.pt.
  • Pires AS; Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal. acgoncalves@fmed.uc.pt.
  • Abrantes AM; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal. acgoncalves@fmed.uc.pt.
  • Coucelo M; 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.
  • Abrunhosa A; Coimbra Institute for Clinical and Biomedical Research (iCBR) - Research Area of Environment Genetics and Oncobiology (CIMAGO), FMUC, University of Coimbra, Coimbra, Portugal.
  • Botelho MF; Clinical Academic Center of Coimbra, CACC, Coimbra, Portugal.
  • Nascimento-Costa JM; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
  • Sarmento-Ribeiro AB; 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.
Med Oncol ; 37(8): 72, 2020 Jul 28.
Article en En | MEDLINE | ID: mdl-32725458
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligomicinas / Leucemia Mieloide Aguda / Desoxiglucosa / Glucosa Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Med Oncol Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligomicinas / Leucemia Mieloide Aguda / Desoxiglucosa / Glucosa Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: Med Oncol Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Portugal Pais de publicación: Estados Unidos