Maintenance of cellular respiration indicates drug resistance in acute myeloid leukemia

• Published in: Leukemia research 2017-11, Vol.62, p.56-63
• Main Authors: Henkenius, Katharina, Greene, Brandon H, Barckhausen, Christina, Hartmann, Raimo, Märken, Melanie, Kaiser, Tom, Rehberger, Miriam, Metzelder, Stephan K, Parak, Wolfgang J, Neubauer, Andreas, Brendel, Cornelia, Mack, Elisabeth
• Format: Article
• Language: English
• Subjects: AML; Cell Line, Tumor; Cell Respiration - physiology; Drug resistance; Drug Resistance, Neoplasm - physiology; Glycolysis - drug effects; Glycolysis - physiology; Humans; Leukemia, Myeloid, Acute - metabolism; Mitochondrial membrane potential; Oxidative Phosphorylation - drug effects; Respiration
• ISSN: 0145-2126; 1873-5835
• DOI: 10.1016/j.leukres.2017.09.021

•Drug resistance in AML is investigated at the level of cellular metabolism.•Resistant AML cells maintained oxidative metabolism upon drug exposure.•Primary AML blasts displayed only low glycolytic activity.•Oxidative phosphorylation appears to be the primary bioenergetic pathway in AML.•Inhibition of oxidative metabolic pathways may overcome drug resistance in AML. Primary resistance to induction therapy is an unsolved clinical problem in acute myeloid leukemia (AML). Here we investigated drug resistance in AML at the level of cellular metabolism in order to identify early predictors of therapeutic response. Using extracellular flux analysis, we compared metabolic drug responses in AML cell lines sensitive or resistant to cytarabine or sorafenib after 24h of drug treatment to a small cell lung cancer (SCLC) cell line exposed to etoposide. Only drug-resistant AML cells maintained oxidative metabolism upon drug exposure while SCLC cells displayed an overall metabolic shift towards glycolysis, i.e. a Warburg effect to escape drug toxicity. Moreover, primary AML blasts displayed very low glycolytic activity, while oxygen consumption was readily detectable, indicating an essential role of oxidative pathways in the bioenergetics of AML blasts. In line with these observations, analysis of the mitochondrial membrane potential using tetramethylrhodamine ethyl ester staining and flow cytometry allowed for clear discrimination between drug sensitive and resistant AML cell line clones and primary blasts after 24h of treatment with cytarabine or sorafenib. Our data reveal a distinct metabolic phenotype of resistant AML cells and suggest that disrupting oxidative metabolism rather than glycolysis may enhance the cytotoxic effects of chemotherapy in AML.