Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized ~(13)C magnetic resonance spectroscopic imaging

摘要

Background. The metabolic phenotype that derives disproportionate energy via glycolysis in solid tumors, including glioma, leads to elevated lactate labeling in metabolic imaging using hyperpolarized [l~(13)C]pyruvate. Although the pyruvate dehydrogenase (PDH)-mediated flux from pyruvate to acetyl coenzyme A can be indirectly measured through the detection of carbon-13 (~(13)C)-labeled bicarbonate, it has proven difficult to visualize ~(13)C-bicarbonate at high enough levels from injected [l-~(13)C]pyruvate for quantitative analysis in brain. The aim of this study is to improve the detection of ~(13)C-labeled metabolites, in particular bicarbonate, in glioma and normal brain in vivo and to measure the metabolic response to dichloroacetate, which upregulates PDH activity. Methods. An optimized protocol for chemical shift imaging and high concentration of hyperpolarized [1-~(13)C] pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Hyperpolarized [1-~(13)C]pyruvate was injected before and 45 min after dichloroacetate infusion. Metabolite ratios of lactate to bicarbonate were calculated to provide improved metrics for characterizing tumor metabolism. Results. Glioma and normal brain were well differentiated by lactate-to-bicarbonate ratio (P = .002, n = 5) as well as bicarbonate (P = .0002) and lactate (P = .001), and a stronger response to dichloroacetate was observed in glioma than in normal brain. Conclusion. Our results clearly demonstrate for the first time the feasibility of quantitatively detecting ~(13)C-bicar-bonate in tumor-bearing rat brain in vivo, permitting the measurement of dichloroacetate-modulated changes in PDH flux. The simultaneous detection of lactate and bicarbonate provides a tool for a more comprehensive analysis of glioma metabolism and the assessment of metabolic agents as anti-brain cancer drugs.