Abstract 1251: Anti-cancer mechanisms of se compounds: A stable isotope-resolved metabolomic (SIRM) approach

Abstract

Abstract Recent rapid advances in analytical tools, especially NMR and mass spectrometry, allow an unprecedented range of metabolites and their transformation pathways to be determined, which transcends classical targeted metabolic studies. We have coupled these tools with stable isotopic tracers [1-3] to investigate the anticancer efficacy and mechanism(s) of different selenium forms using lung adenocarcinoma A549 cells as a model. Selenite (SeO3), methylseleninic acid (MSA) and selenomethionine (SeM) induced distinct changes in steady-state concentrations and 13C labeling patterns of various metabolites including amino & organic acids, nucleotides, antioxidants, as well as phospholipids (PL) and PL metabolites. These changes were determined using a combination of multi-nuclear 2-D NMR, GC-MS, and FT-ICR-MS techniques, which enabled perturbations in multiple metabolic pathways to be simultaneously reconstructed for relating to phenotypic changes. At low µM levels, both SeO3 and MSA inhibited growth, caused cytoskeleton disintegration, and reduced the mitochondrial redox potential in A549 cells. SeM was growth-stimulatory at ≤ 10 µM and inhibited growth but only at 40-fold higher concentration and the extent was much less than MSA or SeO3. These phenotypic differences were related to the early inhibition of glutaminolysis, Krebs cycle, and protein biosynthesis by SeO3, rapid inhibition of pyruvate carboxylation by MSA. SeM had few comparable metabolic effects. Subsequent inhibition of PL biosynthesis was also more substantial in MSA and SeO3 than in SeM-treated cells. The protein and gene expression for key enzymes in these pathways were probed to discern altered metabolic regulations. Thus, the anti-cancer action of MSA differed from that of SeO3 while SeM was not effective against lung cancer cells. The SIRM approach facilitated the resolution of the complex, form-specific anticancer mechanism of Se compounds and is generally applicable to other cancer research problems. 1. Fan, T., et al., Metabolomics-edited transcriptomics analysis of Se anticancer action in human lung cancer cells. Metabolomics Journal, 2005. 1(4): p. 325-339 2. Lane, A.N. and T.W.-M. Fan, Quantification and identification of isotopomer distributions of metabolites in crude cell extracts using 1H TOCSY. Metabolomics, 2007. 3: p. 79-86. 3. Lane, A.N., et al., Isotopomer analysis of lipid biosynthesis by high resolution mass spectrometry and NMR. Analytica Chimica Acta, 2009. 651: p. 201-208. 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 1251. doi:10.1158/1538-7445.AM2011-1251