Hypoglycemic/hypoxic condition in vitro mimicking the tumor microenvironment markedly reduced the efficacy of anticancer drugs.

Tumor tissues are often hypoxic because of defective vasculature. We previously showed that tumor tissues are also often deprived of glucose. The efficacy of anticancer drugs is affected by the tumor microenvironment, partly because of the drug delivery and cellular drug resistance; however, the precise mechanisms remain to be clarified. In the present study, we attempted to clarify whether hypoglycemic/hypoxic condition, which mimics the tumor microenvironment, might induce drug resistance, and if it did, to elucidate the underlying mechanisms. Pancreatic cancer-derived PANC-1 cells were treated with serial dilutions of anticancer drugs and incubated in either normoglycemic (1.0 g/L glucose) or hypoglycemic (0 g/L glucose) and normoxic (21% O(2)) or hypoxic (1% O(2) ) conditions. The 50% inhibitory concentration of gemcitabine was 1000 times higher for PANC-1 cells incubated under the hypoglycemic/hypoxic condition than for those incubated under the normoglycemic/normoxic condition. Conventional anticancer drugs target rapidly growing cells, so that non-proliferating or slowly proliferating cells usually show resistance to drugs. Though the cell cycle was delayed, sufficient cellular uptake and DNA incorporation of gemcitabine occurred under the hypoglycemic/hypoxic condition to cause DNA lesions and S-phase arrest. To overcome hypoglycemic/hypoxia-induced drug resistance, we examined kinase inhibitors targeting Chk1 or cell-survival signaling pathways. Among the compounds examined, the combination of UCN-01 and LY294002 partially sensitized the cells to gemcitabine under the hypoglycemic/hypoxic condition. These findings suggested that the adoption of suitable strategies may enhance the cytotoxicities of clinically used anticancer drugs against cancer cells.