title: Selective elimination of neuroblastoma cells by synergistic effect of Akt kinase inhibitor and tetrathiomolybdate.
abstract: Neuroblastoma is the most common extracranial solid tumour of infancy. Pathological activation of glucose consumption, glycolysis and glycolysis-activating Akt kinase occur frequently in neuroblastoma cells, and these changes correlate with poor prognosis of patients. Therefore, several inhibitors of glucose utilization and the Akt kinase activity are in preclinical trials as potential anti-cancer drugs. However, metabolic plasticity of cancer cells might undermine efficacy of this approach. In this work, we identified oxidative phosphorylation as compensatory mechanism preserving viability of neuroblastoma cells with inhibited glucose uptake/Akt kinase. It was oxidative phosphorylation that maintained intracellular level of ATP and proliferative capacity of these cells. The oxidative phosphorylation inhibitors (rotenone, tetrathiomolybdate) synergized with inhibitor of the Akt kinase/glucose uptake in down-regulation of both viability of neuroblastoma cells and clonogenic potential of cells forming neuroblastoma spheroids. Interestingly, tetrathiomolybdate acted as highly specific inhibitor of oxygen consumption and activator of lactate production in neuroblastoma cells, but not in normal fibroblasts and neuronal cells. Moreover, the reducing effect of tetrathiomolybdate on cell viability and the level of ATP in the cells with inhibited Akt kinase/glucose uptake was also selective for neuroblastoma cells. Therefore, efficient elimination of neuroblastoma cells requires inhibition of both glucose uptake/Akt kinase and oxidative phosphorylation activities. The use of tetrathiomolybdate as a mitochondrial inhibitor contributes to selectivity of this combined treatment, preferentially targeting neuroblastoma cells.
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.|Center for Biological and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Navrátilová
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Karasová
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Kohutková Lánová
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Jiráková
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Budková
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Pacherník
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Šmarda
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.|Center for Biological and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Beneš
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000096:biosynthesis; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008982:Molybdenum / Q000494:pharmacology*; D009447:Neuroblastoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D019344:Lactic Acid; D008982:Molybdenum; D000255:Adenosine Triphosphate; C020809:tetrathiomolybdate; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
keywords: Akt kinase; cell viability; glycolysis; metabolic plasticity; neuroblastoma; oxygen consumption; tetrathiomolybdate