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

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 potenti...

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Veröffentlicht in:Magnetic resonance in medicine 2013-05, Vol.69 (5), p.1443-1450
Hauptverfasser: Matsumoto, Shingo, Saito, Keita, Yasui, Hironobu, Morris, H. Douglas, Munasinghe, Jeeva P., Lizak, Martin, Merkle, Hellmut, Ardenkjaer-Larsen, Jan Henrik, Choudhuri, Rajani, Devasahayam, Nallathamby, Subramanian, Sankaran, Koretsky, Alan P., Mitchell, James B., Krishna, Murali C.
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container_end_page 1450
container_issue 5
container_start_page 1443
container_title Magnetic resonance in medicine
container_volume 69
creator Matsumoto, Shingo
Saito, Keita
Yasui, Hironobu
Morris, H. Douglas
Munasinghe, Jeeva P.
Lizak, Martin
Merkle, Hellmut
Ardenkjaer-Larsen, Jan Henrik
Choudhuri, Rajani
Devasahayam, Nallathamby
Subramanian, Sankaran
Koretsky, Alan P.
Mitchell, James B.
Krishna, Murali C.
description 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 (pO2 < 10 mmHg) in vivo using squamous cell carcinoma (SCCVII)‐bearing mouse model. Metabolic MRI studies using hyperpolarized 13C‐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 (
doi_str_mv 10.1002/mrm.24355
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Douglas ; Munasinghe, Jeeva P. ; Lizak, Martin ; Merkle, Hellmut ; Ardenkjaer-Larsen, Jan Henrik ; Choudhuri, Rajani ; Devasahayam, Nallathamby ; Subramanian, Sankaran ; Koretsky, Alan P. ; Mitchell, James B. ; Krishna, Murali C.</creator><creatorcontrib>Matsumoto, Shingo ; Saito, Keita ; Yasui, Hironobu ; Morris, H. Douglas ; Munasinghe, Jeeva P. ; Lizak, Martin ; Merkle, Hellmut ; Ardenkjaer-Larsen, Jan Henrik ; Choudhuri, Rajani ; Devasahayam, Nallathamby ; Subramanian, Sankaran ; Koretsky, Alan P. ; Mitchell, James B. ; Krishna, Murali C.</creatorcontrib><description>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. 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These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia‐activated drugs. 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Douglas</creatorcontrib><creatorcontrib>Munasinghe, Jeeva P.</creatorcontrib><creatorcontrib>Lizak, Martin</creatorcontrib><creatorcontrib>Merkle, Hellmut</creatorcontrib><creatorcontrib>Ardenkjaer-Larsen, Jan Henrik</creatorcontrib><creatorcontrib>Choudhuri, Rajani</creatorcontrib><creatorcontrib>Devasahayam, Nallathamby</creatorcontrib><creatorcontrib>Subramanian, Sankaran</creatorcontrib><creatorcontrib>Koretsky, Alan P.</creatorcontrib><creatorcontrib>Mitchell, James B.</creatorcontrib><creatorcontrib>Krishna, Murali C.</creatorcontrib><title>EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate</title><title>Magnetic resonance in medicine</title><addtitle>Magn Reson Med</addtitle><description>The hypoxic nature of tumors results in treatment resistance and poor prognosis. 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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 (&lt;5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia‐activated drugs. 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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 (&lt;5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia‐activated drugs. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>22692861</pmid><doi>10.1002/mrm.24355</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record>
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subjects 3-bromopyruvate
Animals
Antineoplastic Agents - therapeutic use
Biomarkers, Tumor - metabolism
Carbon Radioisotopes - pharmacokinetics
Carcinoma, Squamous Cell - diagnosis
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - metabolism
Cell Line, Tumor
Electron Spin Resonance Spectroscopy - methods
EPR imaging
Glycolysis - drug effects
HIF-1
hyperpolarized 13C MRI
Magnetic Resonance Imaging - methods
MCT1
MCT1, tumor hypoxia
Mice
Molecular Imaging - methods
Oxygen - metabolism
Pyruvates - therapeutic use
Pyruvic Acid - metabolism
Radiopharmaceuticals - pharmacokinetics
Reproducibility of Results
Sensitivity and Specificity
Treatment Outcome
tumor hypoxia
title EPR oxygen imaging and hyperpolarized 13C MRI of pyruvate metabolism as noninvasive biomarkers of tumor treatment response to a glycolysis inhibitor 3-bromopyruvate
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