Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models
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Marie-Aline Neveu1, Géraldine De Preter1, Nicolas Joudiou1, Anne Bol2, Jeffery R. Brender3, Keita Saito3, Shun Kishimoto3, Vincent Grégoire2, Bénédicte F. Jordan1, Murali C. Krishna3, Olivier Feron4, Bernard Gallez1
1Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium
2Radiation Oncology Department & Center for Molecular Imaging, Radiotherapy & Oncology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
3Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, USA
4Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium
Bernard Gallez, email: [email protected]
Keywords: tumor metabolism, DCA, 17O MRS, hyperpolarized 13C-MRI, 18F-FDG PET
Received: September 08, 2016 Accepted: October 19, 2016 Published: November 07, 2016
Reverting glycolytic metabolism is an attractive strategy for cancer therapy as upregulated glycolysis is a hallmark in various cancers. Dichloroacetate (DCA), long used to treat lactic acidosis in various pathologies, has emerged as a promising anti-cancer drug. By inhibiting the pyruvate dehydrogenase kinase, DCA reactivates the mitochondrial function and decreases the glycolytic flux in tumor cells resulting in cell cycle arrest and apoptosis. We recently documented that DCA was able to induce a metabolic switch preferentially in glycolytic cancer cells, leading to a more oxidative phenotype and decreasing proliferation, while oxidative cells remained less sensitive to DCA treatment. To evaluate the relevance of this observation in vivo, the aim of the present study was to characterize the effect of DCA in glycolytic MDA-MB-231 tumors and in oxidative SiHa tumors using advanced pharmacodynamic metabolic biomarkers. Oxygen consumption, studied by 17O magnetic resonance spectroscopy, glucose uptake, evaluated by 18F-FDG PET and pyruvate transformation into lactate, measured using hyperpolarized 13C-magnetic resonance spectroscopy, were monitored before and 24 hours after DCA treatment in tumor bearing mice. In both tumor models, no clear metabolic shift was observed. Surprisingly, all these imaging parameters concur to the conclusion that both glycolytic tumors and oxidative tumors presented a similar response to DCA. These results highlight a major discordance in metabolic cancer cell bioenergetics between in vitro and in vivo setups, indicating critical role of the local microenvironment in tumor metabolic behaviors.
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