title: Low-glucose conditions of tumor microenvironment enhance cytotoxicity of tetrathiomolybdate to neuroblastoma cells.
abstract: Growth of tumor cells depends on sufficient supply of fermentable substrate, such as glucose. This provokes development of new anticancer therapies based on dietary restrictions. However, some tumor cells can lower their glucose dependency and activate processes of ATP formation/saving to retain viability even in limited glucose supply. In addition, tumor cells often lose sensitivity to many conventional anticancer drugs in the low-glucose conditions. Thus, development of the drugs effectively killing the tumor cells in nutrient-limited conditions is necessary. In this study, we show an enhanced cytotoxicity of tetrathiomolybdate, the drug exhibiting antiangiogenic and tumor-suppressing effects, to neuroblastoma SH-SY5Y and SK-N-BE(2) cells in the low-glucose conditions. This preference results from the tetrathiomolybdate-induced upregulation of cell dependency on glucose. The cells treated with tetrathiomolybdate increase the uptake of glucose, production of lactate, activate the Akt- and AMPK-signaling pathways and downregulate COX IV. In cells growing in the low-glucose conditions, these events result in significant decrease of the intracellular ATP supply and apoptosis. We propose tetrathiomolybdate as suitable agent to be used in combination with dietary restrictions in therapy of neuroblastoma.
authors.affiliation: Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
authors.forename: Jarmila
authors.initials: J
authors.lastname: Navrátilová
authors.forename: Tereza
authors.initials: T
authors.lastname: Hankeová
authors.forename: Petr
authors.initials: P
authors.lastname: Beneš
authors.forename: Jan
authors.initials: J
authors.lastname: Smarda
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy; D008982:Molybdenum / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D020533:Angiogenesis Inhibitors; D008982:Molybdenum; C020809:tetrathiomolybdate; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose