Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype

摘要: Background and Purpose The testing of anticancer compounds in vitro is usually performed hyperglycaemic cell cultures, although many tumours their vivo microenvironments are hypoglycaemic. Here, we have assessed, cultures tumour cells, the effects reduced glucose levels on resistance to drugs investigated underlying cellular mechanisms. Experimental Approach PIK3CA mutant (AGS, HGC27), wild-type (MKN45, NUGC4) gastric cancer cells were cultured high-glucose (HG, 25mM) or low-glucose (LG, 5mM) media tested for sensitivity two cytotoxic compounds, 5-fluorouracil (5-FU) carboplatin, PI3K/mTOR inhibitor, PI103 mTOR Ku-0063794. Key Results All had increased 5-FU carboplatin when LG compared with HG conditions despite having similar growth cycle characteristics. On treatment Ku-0063794, only displayed conditions. selectively p-mTOR, p-S6, p-4EBP1, GLUT1 lactate production, reactive oxygen species, consistent glycolysis. Combination analysis indicated Ku-0063794 synergistic only. Synergism was accompanied by signalling autophagy. Conclusions Implications Hypoglycaemia agents, especially a high dependence Dual inhibition pathway may be able attenuate such hypoglycaemia-associated resistance.