Enhanced Sensitivity of Metastatic Cells During Anchorage-Independent Growth to Glycolysis Inhibitors Is Limited by the Emergence of a Resistant Subpopulation

Background: The predominance of aerobic glycolysis over oxidative phosphorylation (the Warburg effect) is characteristic of almost all invasive forms of cancer. The specificity of cancer (especially metastatic) cell energy metabolism represents multiple targets for therapeutic intervention using glycolysis inhibitors. Although the transition of cells to the bloodstream (i.e., anchorage-independent growth) is an important step of the metastatic cascade, the question of the cytotoxic efficacy of glycolysis inhibitors against these cells remains largely open. Methods. The cytotoxicity of 2-deoxy-D-glucose, sodium oxamate, metformin, cisplatin, and paclitaxel against high and low metastatic Lewis lung carcinoma cells during anchorage-independent growth (using polyHEMA coated plates) compared to anchorage-dependent growth was studied. The survival, proliferative activity, metabolic plasticity, and FTIR-ATR spectra of the sodium oxamate-resistant cells under different growth conditions were investigated Results. Unlike cisplatin and paclitaxel (which are the basic drugs for the treatment of lung cancer) glycolysis inhibitors such as 2-deoxy-D-glucose and sodium oxamate exhibit high cytotoxicity against carcinoma cells during anchorage-independent growth (compared to anchorage-dependent growth), which correlates with an enhanced glucose consumption rate of these cells. The cytotoxicity of glycolysis inhibitors was shown to be limited by the emergence of resistant cells whose survival was maintained at low glucose consumption rates especially in cells under anchorage-independent growth, most likely due to their ability to activate glutaminolysis. Conclusions. The enhanced cytotoxicity of glycolysis inhibitors against cells during anchorage-independent growth and the emergence of resistant cells, whose survival is presumably related to the activation of mitochondrial metabolism, indicates the potential antimetastatic efficacy of a combination of glycolysis and OXPHOS inhibitors