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Open AccessArticle

Tracing Nutrient Flux Following Monocarboxylate Transporter-1 Inhibition with AZD3965

1
Division of Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
2
Cancer Metabolism Research Unit, Cancer Research UK Beatson Institute, Switchback Rd, Glasgow G61 1BD, UK
3
Molecular and Cellular Oncogenesis, Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA
4
Biological Imaging Centre, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(6), 1703; https://doi.org/10.3390/cancers12061703
Received: 11 May 2020 / Revised: 22 June 2020 / Accepted: 24 June 2020 / Published: 26 June 2020
(This article belongs to the Special Issue Cancer Molecular Imaging)
The monocarboxylate transporter 1 (MCT1) is a key element in tumor cell metabolism and inhibition of MCT1 with AZD3965 is undergoing clinical trials. We aimed to investigate nutrient fluxes associated with MCT1 inhibition by AZD3965 to identify possible biomarkers of drug action. We synthesized an 18F-labeled lactate analogue, [18F]-S-fluorolactate ([18F]-S-FL), that was used alongside [18F]fluorodeoxyglucose ([18F]FDG), and 13C-labeled glucose and lactate, to investigate the modulation of metabolism with AZD3965 in diffuse large B-cell lymphoma models in NOD/SCID mice. Comparative analysis of glucose and lactate-based probes showed a preference for glycolytic metabolism in vitro, whereas in vivo, both glucose and lactate were used as metabolic fuel. While intratumoral L-[1-13C]lactate and [18F]-S-FL were unchanged or lower at early (5 or 30 min) timepoints, these variables were higher compared to vehicle controls at 4 h following treatment with AZD3965, which indicates that inhibition of MCT1-mediated lactate import is reversed over time. Nonetheless, AZD3965 treatment impaired DLBCL tumor growth in mice. This was hypothesized to be a consequence of metabolic strain, as AZD3965 treatment showed a reduction in glycolytic intermediates and inhibition of the TCA cycle likely due to downregulated PDH activity. Glucose ([18F]FDG and D-[13C6]glucose) and lactate-based probes ([18F]-S-FL and L-[1-13C]lactate) can be successfully used as biomarkers for AZD3965 treatment. View Full-Text
Keywords: monocarboxylate transporter 1; cancer metabolism; lactate; glycolysis; AZD3965; diffuse large B-cell lymphoma; metabolic flux; positron emission tomography (PET) monocarboxylate transporter 1; cancer metabolism; lactate; glycolysis; AZD3965; diffuse large B-cell lymphoma; metabolic flux; positron emission tomography (PET)
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Braga, M.; Kaliszczak, M.; Carroll, L.; Schug, Z.T.; Heinzmann, K.; Baxan, N.; Benito, A.; Valbuena, G.N.; Stribbling, S.; Beckley, A.; Mackay, G.; Mauri, F.; Latigo, J.; Barnes, C.; Keun, H.; Gottlieb, E.; Aboagye, E.O. Tracing Nutrient Flux Following Monocarboxylate Transporter-1 Inhibition with AZD3965. Cancers 2020, 12, 1703.

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