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Consideration of metabolite efflux in radiolabelled choline kinetics

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Title: Consideration of metabolite efflux in radiolabelled choline kinetics
Authors: Aboagye, E
Li, Y
Inglese, M
Dubash, S
Barnes, C
Brickute, D
Costa Braga, M
Wang, N
Beckley, A
Heinzmann, K
Allot, L
Lu, H
Chen, C
Fu, R
Fu, R
Carroll, L
Item Type: Journal Article
Abstract: Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore may confound uptake of choline radiotracer [ 18F]fluoromethyl-[1,2- 2H4]-choline ([ 18 F]-D4-FCH). The aim of this study was to investigate how hypoxia affects choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [ 18 F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and efflux of [18 F]-D4-FCH and its phosphorylated product [ 18F]-D4-FCHP. Effects of hypoxia on [18 F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer, MDA-MB-231 cells. Mechanisms of radiotracer efflux were assessed by cell uptake and immunofluorescence in vitro, and examined in vivo (N=24). Mathematical modelling methodology was further developed to verify efflux hypothesis using [18 F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (N=17). We report a novel finding involving export of phosphorylated [18F]-D4-FCH, [18 F]-D4-FCHP, via HIF-1α-responsive efflux transporters including ABCB4 when HIF-1α level is augmented. This is supported by graphical analysis of human data with a compartmental model (M2T6k+k5) that accounts for efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting consideration of efflux in modelling of radiotracer dynamics.
Issue Date: 12-Aug-2021
Date of Acceptance: 6-Aug-2021
URI: http://hdl.handle.net/10044/1/90990
DOI: 10.3390/pharmaceutics13081246
ISSN: 1999-4923
Publisher: MDPI AG
Start Page: 1
End Page: 18
Journal / Book Title: Pharmaceutics
Volume: 13
Issue: 8
Copyright Statement: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Sponsor/Funder: Cancer Research UK
Funder's Grant Number: 16584
Keywords: Science & Technology
Life Sciences & Biomedicine
Pharmacology & Pharmacy
choline kinase
hypoxia
efflux
POSITRON-EMISSION-TOMOGRAPHY
BINDING CASSETTE TRANSPORTERS
PROSTATE-CANCER
KINASE ALPHA
MALIGNANT-TRANSFORMATION
PHOSPHOLIPID-METABOLISM
MULTIDRUG-RESISTANCE
TRANSFER CONSTANTS
HYPOXIA
EXPRESSION
choline kinase
efflux
hypoxia
1115 Pharmacology and Pharmaceutical Sciences
Publication Status: Published
Online Publication Date: 2021-08-12
Appears in Collections:Department of Surgery and Cancer
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons