Cisplatin (CDDP), a platinum-based drug, is used for the treatment of a wide range of human solid malignancies including ovarian cancer. However, many patients develop drug resistance in CDDP treatment, leading to therapeutic failure. The research around the mechanism of CDDP resistance has been conducted, but it is rare to find feasible treatment methods that allow the resistant cancer cell return to normal CDDP sensitivity. In order to overcome resistance and improve the anticancer efficacy, the mechanism of CDDP resistance should be further investigated. In this study, we used epithelial ovarian cancer cell line A2780 and CDDP resistant cell line A2780cis. The resistance of A2780cis cells was about 20 times higher than that of its parent A2780 cells. We examined the metabolic profiles in the both cell lines with or without CDDP by capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). In the presence of CDDP, A2780 cells exhibited increases on intermediary metabolites of glycolytic pathway and TCA cycle except succinate, compared with A2780cis cells. These results indicated that different sensibility may lead to different energy metabolism on CDDP response. At the same time, we found that intracellular glutamine levels which is used for energy conversion in cancer cells, was 30 times higher in resistant cells. This led us focus on the role of glutamine in CDDP resistance. Furthermore, our results of sensitivity test showed that CDDP sensitivity of the resistant cells was increased in low-glutamine culture or by glutaminase inhibitor. The results revealed that the glutamine metabolism was related to CDDP resistance in A2780cis cells. By analyzing and comparing the metabolites of A2780 and A2780cis cells in low-glutamine cultured, we found glutathione (GSH) significantly reduced in A2780cis cells compared with general culture. GSH have been proved to be effective to improve the sensitivity by helping CDDP export and inactivate. We considered that glutamine inhibition resulted in an increase in CDDP sensitivity, via generating a reduction in GSH levels. Therefore, glutamine metabolism is important for CDDP sensitivity in resistant cells, and it might be a novel therapeutic target against the CDDP resistance.
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