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.