¹⁸FDG a PET tumor diagnostic tracer is not a substrate of the ABC transporter P-glycoprotein

Abstract

2-[(18)F]fluoro-2-deoxy-d-glucose ((18)FDG) is a tumor diagnostic radiotracer of great importance in both diagnosing primary and metastatic tumors and in monitoring the efficacy of the treatment. P-glycoprotein (Pgp) is an active transporter that is often expressed in various malignancies either intrinsically or appears later upon disease progression or in response to chemotherapy. Several authors reported that the accumulation of (18)FDG in P-glycoprotein (Pgp) expressing cancer cells (Pgp(+)) and tumors is different from the accumulation of the tracer in Pgp nonexpressing (Pgp(-)) ones, therefore we investigated whether (18)FDG is a substrate or modulator of Pgp pump. Rhodamine 123 (R123) accumulation experiments and ATPase assay were used to detect whether (18)FDG is substrate for Pgp. The accumulation and efflux kinetics of (18)FDG were examined in two different human gynecologic (A2780/A2780AD and KB-3-1/KB-V1) and a mouse fibroblast (3T3 and 3T3MDR1) Pgp(+) and Pgp(-) cancer cell line pairs both in cell suspension and monolayer cultures. We found that (18)FDG and its derivatives did not affect either the R123 accumulation in Pgp(+) cells or the basal and the substrate stimulated ATPase activity of Pgp supporting that they are not substrates or modulators of the pump. Measuring the accumulation and efflux kinetics of (18)FDG in different Pgp(+) and Pgp(-) cell line pairs, we have found that the Pgp(+) cells exhibited significantly higher (p⩽0.01) (18)FDG accumulation and slightly faster (18)FDG efflux kinetics compared to their Pgp(-) counterparts. The above data support the idea that expression of Pgp may increase the energy demand of cells resulting in higher (18)FDG accumulation and faster efflux. We concluded that (18)FDG and its metabolites are not substrates of Pgp.

Keywords: (18)FDG; 2-Chloro-2-deoxy-d-glucose (PubChem CID: 151933); 2-Deoxy-d-glucose (PubChem CID: 108223); 2-Fluoro-2-deoxy-d-glucose (PubChem CID: 170049); Cyclosporin A (PubChem CID: 5284373); Doxorubicin (PubChem CID: 31703); Gynecologic cancer cells; Multidrug resistance; PET tumordiagnostic tracer; Pgp substrate; Rhodamine 123 (PubChem CID: 65217); Verapamil hydrochloride (PubChem CID: 62969); Vinblastine (PubChem CID: 241903); [(18)F]Fluoro-2-deoxy-2-d-glucose (PubChem CID: 3232583).