title: Multi-modality imaging to assess metabolic response to dichloroacetate treatment in tumor models.
abstract: 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.
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Marie-Aline
authors.initials: MA
authors.lastname: Neveu
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Géraldine
authors.initials: G
authors.lastname: De Preter
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Joudiou
authors.affiliation: Radiation Oncology Department & Center for Molecular Imaging, Radiotherapy & Oncology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Bol
authors.affiliation: Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, USA.
authors.forename: Jeffery R
authors.initials: JR
authors.lastname: Brender
authors.affiliation: Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, USA.
authors.forename: Keita
authors.initials: K
authors.lastname: Saito
authors.affiliation: Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, USA.
authors.forename: Shun
authors.initials: S
authors.lastname: Kishimoto
authors.affiliation: Radiation Oncology Department & Center for Molecular Imaging, Radiotherapy & Oncology, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Grégoire
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Bénédicte F
authors.initials: BF
authors.lastname: Jordan
authors.affiliation: Radiation Biology Branch, National Cancer Institute, NIH, Bethesda, USA.
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
authors.affiliation: Pole of Pharmacology and Therapeutics, Institute of Experimental and Clinical Research, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
authors.affiliation: Biomedical Magnetic Resonance Research Group, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D000072078:Positron Emission Tomography Computed Tomography; D011237:Predictive Value of Tests; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid / Q000378:metabolism; D013997:Time Factors; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D019289:Pyruvic Acid; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases
keywords: 17O MRS; 18F-FDG PET; DCA; hyperpolarized 13C-MRI; tumor metabolism