Overcoming 5-Fu resistance in human non-small cell lung cancer cells by the combination of 5-Fu and cisplatin through the inhibition of glucose metabolism.

5-Fu is a pyrimidine analog which is wildly used in the treatment of cancers. The development of strategies that increase its anticancer activity has been studied over the past 20 years. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. In this study, we investigate the glucose metabolic profiles of non-small cell lung cancer cells in response to 5-Fu and cisplatin. Interestingly, the glucose metabolism of A549 cells is activated by 5-Fu treatment but suppressed by cisplatin treatment. We generalize 5-Fu-resistant and cisplatin-resistant cell lines from A549 cells. The glucose metabolism in 5-Fu-resistant cells is increased but decreased in cisplatin-resistant cells. In addition, glycolysis inhibition sensitizes lung cancer cells to 5-Fu. Importantly, we report a synergistic inhibitory effect on lung cancer cells by the combination of 5-Fu with cisplatin through the suppression of glucose metabolism both in vitro and in vivo. Moreover, restoration of glucose metabolism by overexpression of glycolytic key enzymes renders A549 cells resistant to 5-Fu. In summary, our study indicates that glycolysis inhibition contributes to the synergistic antitumor effect of combinational therapy, and targeting glycolysis could be an effective strategy for overcoming 5-Fu resistance in cancer therapy.