Consideration of metabolite efflux in radiolabelled choline kinetics
| العنوان: | Consideration of metabolite efflux in radiolabelled choline kinetics |
|---|---|
| المؤلفون: | Ning Wang, Chris P. Barnes, Suraiya Dubash, Diana Brickute, Cen Chen, Marta Braga, Eric O. Aboagye, Marianna Inglese, Yunqing Li, Kathrin Heinzmann, Ruisi Fu, Alice Beckley, Haonan Lu, Louis Allott, Laurence Carroll |
| المساهمون: | Cancer Research UK |
| المصدر: | Pharmaceutics Volume 13 Issue 8 Pharmaceutics, Vol 13, Iss 1246, p 1246 (2021) |
| بيانات النشر: | MDPI AG, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | EXPRESSION, Choline kinase, Metabolite, Cell, MALIGNANT-TRANSFORMATION, Pharmaceutical Science, Article, chemistry.chemical_compound, PHOSPHOLIPID-METABOLISM, Pharmacy and materia medica, POSITRON-EMISSION-TOMOGRAPHY, In vivo, medicine, BINDING CASSETTE TRANSPORTERS, Choline, Pharmacology & Pharmacy, MULTIDRUG-RESISTANCE, TRANSFER CONSTANTS, Science & Technology, choline kinase, hypoxia, efflux, PROSTATE-CANCER, RS1-441, medicine.anatomical_structure, Biochemistry, chemistry, Cell culture, Efflux, Choline transport, 1115 Pharmacology and Pharmaceutical Sciences, Life Sciences & Biomedicine, KINASE ALPHA |
| الوصف: | 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 the uptake of choline radiotracer [18F]fluoromethyl-[1,2-2H4]-choline ([18F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [18F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [18F]-D4-FCH and its phosphorylated product [18F]-D4-FCHP. The effects of hypoxia on [18F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer MDA-MB-231 cells. The mechanisms of radiotracer efflux were assessed by the cell uptake and immunofluorescence in vitro and examined in vivo (n = 24). The mathematical modelling methodology was further developed to verify the efflux hypothesis using [18F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (n = 17). We report a novel finding involving the export of phosphorylated [18F]-D4-FCH and [18F]-D4-FCHP via HIF-1α-responsive efflux transporters, including ABCB4, when the HIF-1α level is augmented. This is supported by a graphical analysis of human data with a compartmental model (M2T6k + k5) that accounts for the efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting the consideration of efflux in the modelling of radiotracer dynamics. |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::276afc69ae2d9b74c0578b904c079290 http://hdl.handle.net/10044/1/90990 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....276afc69ae2d9b74c0578b904c079290 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |