Abstract
Abstract Platinum-based drugs such as cisplatin, carboplatin and xoaliplatin hav been introduced into clinical trials and their outcomes has progressed the treatment on several tumors, including ovarian cancer. However, cancer cells acquire chemo-resistance in the long term incubation of drugs, which turns out to be the major limitation for cancer therapy. Recent studies have shown that cisplatin can accumulate in mitochondria and induce cytochrome C release, thereby resulting in apoptosis. We found that glutamine plays a vital role in maintaining mitochondrial integrity and function by regulating NAD+ and NADH. Using bioenergetics and isotopomer analysis we show that chemodrugs in presence of glutamine affect oxidative phosphorylation in drug sensitive parental ovarian cancer cells. Addition of NAD+ substrates increased NAD/NADH ratio abrogating cisplatin's effect on cell death and mitochondrial dysfunction. Furthermore, drug resistant cancer cells had relatively higher glutamine dependence when compared with parental cells. Importantly, we found that when glutamine's entry into TCA cycle was inhibited ovarian cancer cells became more sensitive to chemotherapy. Our findings are based on the quantification of metabolites, related to glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acids and nucleotide metabolism, and comparison of these pathways fluxes in drug sensitive and drug resistant ovarian cancer. The insights obtained present a unique opportunity for overcoming the drug resistance limitation in clinical trials in ovarian cancers. Citation Format: Lifeng Yang, Tyler J. Moss, Juan C. Marini, Selanere Mangala, Stephen Wahlig, Julia Win, Dan Su, Anil K. Sood, Prahlad T. Ram, Deepak Nagrath. Glutamine mediated aggressiveness and drug sensitivity in ovarian cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3377. doi:10.1158/1538-7445.AM2014-3377
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