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 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 (<5 mmHg) tumor regions. These results emphasize the importance of noninvasive imaging biomarkers to confirm the action of hypoxia-activated drugs.
Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-1002, USA.
Shingo
S
Matsumoto
Keita
K
Saito
Hironobu
H
Yasui
H Douglas
HD
Morris
Jeeva P
JP
Munasinghe
Martin
M
Lizak
Hellmut
H
Merkle
Jan Henrik
JH
Ardenkjaer-Larsen
Rajani
R
Choudhuri
Nallathamby
N
Devasahayam
Sankaran
S
Subramanian
Alan P
AP
Koretsky
James B
JB
Mitchell
Murali C
MC
Krishna
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods*; D006019:Glycolysis / Q000187:drug effects; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D057054:Molecular Imaging / Q000379:methods; D010100:Oxygen / Q000378:metabolism*; D011773:Pyruvates / Q000627:therapeutic use; D019289:Pyruvic Acid / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002250:Carbon Radioisotopes; D011773:Pyruvates; D019275:Radiopharmaceuticals; C017092:bromopyruvate; D019289:Pyruvic Acid; D010100:Oxygen