• Author: Matsumoto, Shingo

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

  • Author: Saito, Keita

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

  • Author: Yasui, Hironobu

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

  • Author: Morris, H. Douglas

    Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, United States

  • Author: Munasinghe, Jeeva P.

    Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, United States

  • Author: Lizak, Martin

    3Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, United States

  • Author: Merkle, Hellmut

    3Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, United States

  • Author: Ardenkjær-Larsen, Jan Henrik

    Biomedical Engineering, Department of Electrical Engineering, Technical University of Denmark, Ørsteds Plads, 2800, Kgs. Lyngby, Denmark

  • Author: Choudhuri, Rajani

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

  • Author: Devasahayam, Nallathamby

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

  • Author: Subramanian, Sankaran

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

  • Author: Koretsky, Alan P.

    Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, United States

  • Author: Mitchell, James B.

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

  • Author: Krishna, Murali C.

    Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, United States

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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
Publication date2013
Volume69
Issue5
Pages1443-1450
ISSN0740-3194
DOIs
StatePublished
CitationsWeb of Science® Times Cited: 5

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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