EPR oxygen imaging and hyperpolarized (13) C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate.

Shingo Matsumoto, Keita Saito, Hironobu Yasui, H. Douglas Morris, Jeeva P. Munasinghe, Martin Lizak, Hellmut Merkle, Jan Henrik Ardenkjær-Larsen, Rajani Choudhuri, Nallathamby Devasahayam, Sankaran Subramanian, Alan P. Koretsky, James B. Mitchell, Murali C. Krishna

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

The hypoxic nature of tumors results in treatment resistance and poor prognosis. To spare limited oxygen for more crucial pathways, hypoxic cancerous cells suppress mitochondrial oxidative phosphorylation and promote glycolysis for energy production. Thereby, inhibition of glycolysis has the potential to overcome treatment resistance of hypoxic tumors. Here, EPR imaging was used to evaluate oxygen dependent efficacy on hypoxia-sensitive drug. The small molecule 3-bromopyruvate blocks glycolysis pathway by inhibiting hypoxia inducible enzymes and enhanced cytotoxicity of 3-bromopyruvate under hypoxic conditions has been reported in vitro. However, the efficacy of 3-bromopyruvate was substantially attenuated in hypoxic tumor regions (pO(2) < 10 mmHg) in vivo using squamous cell carcinoma (SCCVII)-bearing mouse model. Metabolic MRI studies using hyperpolarized (13) C-labeled pyruvate showed that monocarboxylate transporter-1 is the major transporter for pyruvate and the analog 3-bromopyruvate in SCCVII tumor. The discrepant results between in vitro and in vivo data were attributed to biphasic oxygen dependent expression of monocarboxylate transporter-1 in vivo. Expression of monocarboxylate transporter-1 was enhanced in moderately hypoxic (8-15 mmHg) tumor regions but down regulated in severely hypoxic (<5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia-activated drugs.
Original languageEnglish
JournalMagnetic Resonance in Medicine
Volume69
Issue number5
Pages (from-to)1443-1450
ISSN0740-3194
DOIs
Publication statusPublished - 2013

Keywords

  • Bromopyruvate
  • Hypoxic
  • Tumor
  • Pyruvate
  • Glycolysy
  • EPR imaging
  • Monocarboxylate
  • Monocarboxylate transporter
  • Transporter
  • Oxygen
  • mry
  • Hyperpolarized 13C MRI
  • Biomarker
  • Pyruvate metabolism
  • mmhg

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