Abstract
Background[18F]Fluoromisonidazole ([18F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [18F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [18F]FMISO uptake level varied depending on the cellular glutathione conjugation and excretion ability such as enzyme activity of glutathione-S-transferase and expression levels of multidrug resistance-associated protein 1 (MRP1, an efflux transporter), in addition to the cellular hypoxic state. In this study, we evaluated whether MRP1 activity affected [18F]FMISO PET imaging.MethodsFaDu human pharyngeal squamous cell carcinoma cells were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, incubated with [18F]FMISO for 4 h under hypoxia, and their radioactivity was then measured. FaDu tumor-bearing mice were intravenously injected with [18F]FMISO, and PET/CT images were acquired at 4 h post-injection (1st PET scan). Two days later, the same mice were pretreated with MRP1 inhibitors (cyclosporine A, lapatinib, or MK-571) for 1 h, and PET/CT images were acquired (2nd PET scan).ResultsFaDu cells pretreated with MRP1 inhibitors exhibited significantly higher radioactivity than those without inhibitor treatment (cyclosporine A: 6.91 ± 0.27, lapatinib: 10.03 ± 0.47, MK-571: 10.15 ± 0.44%dose/mg protein, p < 0.01). In the in vivo PET study, the SUVmean ratio in tumors [calculated as after treatment (2nd PET scan)/before treatment of MRP1 inhibitors (1st PET scan)] of the mice treated with MRP1 inhibitors was significantly higher than those of control mice (cyclosporine A: 2.6 ± 0.7, lapatinib: 2.2 ± 0.7, MK-571: 2.2 ± 0.7, control: 1.2 ± 0.2, p < 0.05).ConclusionIn this study, we revealed that MRP1 inhibitors increase [18F]FMISO accumulation in hypoxic cells. This suggests that [18F]FMISO-PET imaging is affected by MRP1 inhibitors independent of the hypoxic state.
Highlights
In solid tumor tissues, a low oxygen concentration region or hypoxic region is known to be related to cancer resistance toward radiotherapy and chemotherapy [1]
In vitro multidrug resistance-associated protein 1 (MRP1) activity assay The %intensity was calculated as the fluorescence intensity/mg protein of the cells pretreated with compounds per the fluorescence intensity/mg protein of the non-treated cells
To consider that MRP1 mediates the efflux of agents conjugated with glutathione out of cells, we hypothesized that [18F]FMISO uptake in hypoxic cells might be correlated inversely with MRP1 activity, that is, the agents blocking MRP1 activity affect the efflux of [18F]FMISO in hypoxic regions of tumors
Summary
A low oxygen concentration region or hypoxic region is known to be related to cancer resistance toward radiotherapy and chemotherapy [1]. Precise monitoring of hypoxic states in tumor tissue by. We previously investigated the accumulation mechanism of [18F] FMISO using a combination of imaging mass spectrometry and radioisotope analysis and found that [ 18F]FMISO taken up by hypoxic cells was metabolized mainly to be Shimizu et al EJNMMI Res (2021) 11:9 the glutathione conjugate of reduced FMISO [5]. We performed a cellular uptake study of [18F]FMISO with several types of tumor cells whose glutathione conjugation and excretion ability, such as enzyme activity of glutathione-S-transferase and expression levels of multidrug resistance-associated protein 1 (MRP1), differed [6, 7]. The [18F]FMISO uptake level varied depending on the glutathione conjugation and excretion ability of cells, in addition to the cellular hypoxic state
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