Study of monoglutathionyl conjugates TC-99M-sestamibi and TC-99M-tetrofosmin transport mediated by the multidrug resistance-associated protein isoform 1 in glioma cells

Abstract

The emergence of multidrug resistance (MDR) is a major obstacle to successful chemotherapy of malignant glioma tumors. Overexpression of the multidrug resistance-associated protein isoform 1 (MRP1), associated with a high level of intracellular glutathione (GSH), is a well-characterized mechanism of MDR in glioma cells. Previously, we have investigated the role of GSH and MRP1 in the accumulation of two radiopharmaceuticals classically used in nuclear medicine: (99m)Tc-sestamibi (MIBI) and (99m)Tc-tetrofosmin (TFOS), in a model of glioma cell lines. Although the involvement of GSH in MRP1-mediated transport of the two radiopharmaceuticals has been demonstrated, the exact transport mechanisms involving phase II (conjugation) and phase III (efflux) detoxification of these lipophilic cations has not been fully elucidated. To clarify the difference of release kinetics observed between MIBI and TFOS, we have studied the efficiency of formation of monogluthationyl conjugates mediated by glutathione S-transferses (GSTs). Our results clearly demonstrate that, in our model, the main efflux mechanism for radiopharmaceuticals is on monoglutathionyl-conjugates of MIBI (MIBI-SG) and TFOS (TFOS-SG). These mechanisms involving MRP1, and the phase II of detoxification is not efficient for TFOS in resistant glioma cells. A relatively slower catalytic efficiency of formation of TFOS-SG conjugate (0.006%.s(-1)) prevents its expulsion, contrary to MIBI (0.133%.s(-1)), suggesting that TFOS should be interesting in the detection and management of patients with high-grade glioma.