Tyrosine Kinase Inhibitors Reduce Glucose Uptake by Binding to an Exofacial Site on hGLUT‐1: Influence on 18F‐FDG PET Uptake
| Autor: | Jack A. Tuszynski, Michael B. Sawyer, Vijaya L. Damaraju, Philip Winter, Jordane Preto, Alexander B.J. McEwan, Maral Aminpour, Michelle Kuzma |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
030213 general clinical medicine
Glucose uptake RM1-950 Pharmacology 030226 pharmacology & pharmacy General Biochemistry Genetics and Molecular Biology Pazopanib 03 medical and health sciences 0302 clinical medicine Non-competitive inhibition medicine General Pharmacology Toxicology and Pharmaceutics Chemistry General Neuroscience Imatinib General Medicine Temsirolimus 3. Good health respiratory tract diseases Glucose binding Nilotinib Therapeutics. Pharmacology Public aspects of medicine RA1-1270 Tyrosine kinase medicine.drug |
| Zdroj: | Clinical and Translational Science, Vol 14, Iss 3, Pp 847-858 (2021) |
| ISSN: | 1752-8054 1752-8062 |
| Popis: | Positron emission tomography (PET) using 2-deoxy-2-[18 F]fluoro-d-glucose ([18 F]FDG), a marker of energy metabolism and cell proliferation, is routinely used in the clinic to assess patient response to chemotherapy and to monitor tumor growth. Treatment with some tyrosine kinase inhibitors (TKIs) causes changes in blood glucose levels in both nondiabetic and diabetic patients. We evaluated the interaction of several classes of TKIs with human glucose transporter-1 (hGLUT-1) in FaDu and GIST-1 cells by measuring [3 H]2-deoxy-d-glucose ([3 H]2-DG) and [3 H]FDG uptake. Uptake of both was inhibited to varying extents by the TKIs, and representative TKIs from each class showed competitive inhibition of [3 H]2-DG uptake. In GIST-1 cells, [3 H]FDG uptake inhibition by temsirolimus and nilotinib was irreversible, whereas inhibition by imatinib, gefitinib, and pazopanib was reversible. Molecular modeling studies showed that TKIs form multiple hydrogen bonds with polar residues of the sugar binding site (i.e., Q161, Q282, Q283, N288, N317, and W388), and van der Waals interactions with the H-pocket site. Our results showed interaction of TKIs with amino acid residues at the glucose binding site to inhibit glucose uptake by hGLUT-1. We hypothesize that inhibition of hGLUT-1 by TKIs could alter glucose levels in patients treated with TKIs, leading to hypoglycemia and fatigue, although further studies are required to evaluate roles of other SLC2 and SLC5 members. In addition, TKIs could affect tumor [18 F]FDG uptake, increasingly used as a marker of tumor response. The hGLUT-1 inhibition by TKIs may have implications for routine [18 F]FDG-PET monitoring of tumor response in patients. |
| Databáze: | OpenAIRE |
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