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

Jae Mo Park, Lawrence D. Recht, Sonal Josan, Milton Merchant, Taichang Jang, Yi Fen Yen, Ralph E. Hurd, Daniel M. Spielman, Dirk Mayer

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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 [1-13C]pyruvate. Although the pyruvate dehydrogenase (PDH)-mediated flux from pyruvate to acetyl coenzyme A can be indirectly measured through the detection of carbon-13 ( 13C)-labeled bicarbonate, it has proven difficult to visualize 13C-bicarbonate at high enough levels from injected [1-13C]pyruvate for quantitative analysis in brain. The aim of this study is to improve the detection of 13C-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- 13C] pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Hyperpolarized [1- 13C]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 werewell 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 13C-bicarbonate in tumor-bearing rat brain in vivo, permitting the measurement of dichloroacetate-modulated changes in PDHflux. 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.

Original languageEnglish (US)
Pages (from-to)433-441
Number of pages9
JournalNeuro-oncology
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

Fingerprint

Bicarbonates
Glioma
Pyruvic Acid
Magnetic Resonance Imaging
Lactic Acid
Brain
Oxidoreductases
Neoplasms
Acetyl Coenzyme A
Glycolysis
Brain Neoplasms
Up-Regulation
Carbon
Phenotype
Pharmaceutical Preparations

Keywords

  • Bicarbonate
  • Dichloroacetate
  • Glioma
  • Hyperpolarized C
  • Pyruvate

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging. / Park, Jae Mo; Recht, Lawrence D.; Josan, Sonal; Merchant, Milton; Jang, Taichang; Yen, Yi Fen; Hurd, Ralph E.; Spielman, Daniel M.; Mayer, Dirk.

In: Neuro-oncology, Vol. 15, No. 4, 01.04.2013, p. 433-441.

Research output: Contribution to journalArticle

Park, JM, Recht, LD, Josan, S, Merchant, M, Jang, T, Yen, YF, Hurd, RE, Spielman, DM & Mayer, D 2013, 'Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging', Neuro-oncology, vol. 15, no. 4, pp. 433-441. https://doi.org/10.1093/neuonc/nos319
Park, Jae Mo ; Recht, Lawrence D. ; Josan, Sonal ; Merchant, Milton ; Jang, Taichang ; Yen, Yi Fen ; Hurd, Ralph E. ; Spielman, Daniel M. ; Mayer, Dirk. / Metabolic response of glioma to dichloroacetate measured in vivo by hyperpolarized 13C magnetic resonance spectroscopic imaging. In: Neuro-oncology. 2013 ; Vol. 15, No. 4. pp. 433-441.
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abstract = "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 [1-13C]pyruvate. Although the pyruvate dehydrogenase (PDH)-mediated flux from pyruvate to acetyl coenzyme A can be indirectly measured through the detection of carbon-13 ( 13C)-labeled bicarbonate, it has proven difficult to visualize 13C-bicarbonate at high enough levels from injected [1-13C]pyruvate for quantitative analysis in brain. The aim of this study is to improve the detection of 13C-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- 13C] pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Hyperpolarized [1- 13C]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 werewell 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 13C-bicarbonate in tumor-bearing rat brain in vivo, permitting the measurement of dichloroacetate-modulated changes in PDHflux. 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.",
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AU - Josan, Sonal

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AU - Jang, Taichang

AU - Yen, Yi Fen

AU - Hurd, Ralph E.

AU - Spielman, Daniel M.

AU - Mayer, Dirk

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AB - 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 [1-13C]pyruvate. Although the pyruvate dehydrogenase (PDH)-mediated flux from pyruvate to acetyl coenzyme A can be indirectly measured through the detection of carbon-13 ( 13C)-labeled bicarbonate, it has proven difficult to visualize 13C-bicarbonate at high enough levels from injected [1-13C]pyruvate for quantitative analysis in brain. The aim of this study is to improve the detection of 13C-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- 13C] pyruvate were used to improve measurements of lactate and bicarbonate in C6 glioma-transplanted rat brains. Hyperpolarized [1- 13C]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 werewell 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 13C-bicarbonate in tumor-bearing rat brain in vivo, permitting the measurement of dichloroacetate-modulated changes in PDHflux. 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.

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