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

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-(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 [1-(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-bicarbonate 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.

• Authors: Jae Mo Park, Lawrence D Recht, Sonal Josan, Milton Merchant, Taichang Jang, Yi-Fen Yen, Ralph E Hurd, Daniel M Spielman, Dirk Mayer
• Journal: Neuro-oncology (Neuro Oncol) Vol. 15 Issue 4 Pg. 433-41 (Apr 2013) ISSN: 1523-5866 [Electronic] England
• PMID: 23328814 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Carbon Radioisotopes
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvates
• Acetyl Coenzyme A
• Dichloroacetic Acid
• Protein Serine-Threonine Kinases

Topics

• Acetyl Coenzyme A (metabolism)
• Animals
• Brain (drug effects, metabolism, pathology)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Carbon Radioisotopes
• Dichloroacetic Acid (pharmacology)
• Glioma (drug therapy, metabolism, pathology)
• Magnetic Resonance Imaging
• Male
• Mitochondria (drug effects, metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvates (metabolism)
• Rats
• Rats, Wistar
• Tumor Cells, Cultured