Matsumoto, Shingo3; Saito, Keita3; Yasui, Hironobu3; Morris, H. Douglas4; Munasinghe, Jeeva P.4; Lizak, Martin4; Merkle, Hellmut4; Ardenkjær-Larsen, Jan Henrik5; Choudhuri, Rajani3; Devasahayam, Nallathamby3; Subramanian, Sankaran3; Koretsky, Alan P.4; Mitchell, James B.3; Krishna, Murali C.3
1 Department of Electrical Engineering, Technical University of Denmark2 Biomedical Engineering, Department of Electrical Engineering, Technical University of Denmark3 National Cancer Institute4 National Institute of Neurological Disorder and Stroke5 Center for Hyperpolarization in Magnetic Resonance, Center, Technical University of Denmark
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.
Magnetic Resonance in Medicine, 2013, Vol 69, Issue 5, p. 1443-1450