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

• Published in: Medical oncology (Northwood, London, England) London, England), 2020-08, Vol.37 (8), p.72-72, Article 72
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Cell cycle; Gene expression; Hematology; Internal Medicine; Leukemia; Medicine; Medicine & Public Health; Metabolism; Mutation; Oncology; Original Paper; Pathology; Reactive oxygen species
• ISSN: 1357-0560; 1559-131X
• DOI: 10.1007/s12032-020-01394-6

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 18 F-FDG and RT-PCR/qPCR, respectively. No IDH1/2 exon 4 mutations were detected. HEL cells had the highest 18 F-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 18 F-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.