Abstract 4087: Metabolic changes associated with acquired cisplatin resistance

Abstract

Abstract Although cisplatin is the drug of choice in treating lung cancer patients, acquired resistance appears to be a common and serious drawback to its effectiveness in the clinic. Using two pairs of cisplatin sensitive and resistant lung cancer cell lines developed in vitro, we have found significantly lowered hexokinase II (HKII) levels in both resistant cell lines. As a consequence of lowered HKII, these cell lines, when grown under anaerobic conditions, are markedly more sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2DG) than their parental cell lines from which they were derived. This was our first indication that lowered HKII levels in these cisplatin resistant cells has metabolic consequences in different environmental conditions. Thus, it appears that a fundamental difference in glucose metabolism is associated with resistance to cisplatin in these cell lines. It is the aim of this study to explore whether reduced HKII is a common occurrence in cisplatin resistant cells and whether these differences uncover metabolic targets that can be exploited for therapeutic gain. Much like the Atkins diet, when carbohydrates are lowered or glycolysis is inhibited, other sources of energy such as fatty acids and amino acids can be used to maintain cell viability. A trypan blue cytotoxicity assay was used to determine the sensitivity of our cisplatin resistant cell lines to a pharmacological inhibitor, etomoxir, toward fatty acid oxidation. Thus, we tested and found that one of these cisplatin resistant cell lines is sensitive to interference with fatty acid oxidation. Next, we placed our cell lines in glutamine free medium, and found that the second cisplatin resistant cell line is sensitive to glutamine deprivation. Moreover, when lactate production was measured in anaerobic conditions, cisplatin resistant cell lines produced less lactate when challenged with the glycolytic inhibitor, 2DG, than their cisplatin sensitive parental cell lines. Overall, our results indicate that lowered HKII levels in two cisplatin resistant cell lines appear to be associated with a decreased reliance on glucose metabolism, with a shift to either fatty acid oxidation or glutaminolysis. Moreover, these cisplatin resistant cells are sensitive to glycolytic inhibition when placed in oxygen-deprived conditions. Thus, these new metabolic targets may be exploited for therapeutic gain in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4087. doi:10.1158/1538-7445.AM2011-4087