Increased [18F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors

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. Methods FaDu 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). Results FaDu 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). Conclusion In 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.

Acute Hypoxia Alters Extracellular Vesicle Signatures and the Brain Citrullinome of Naked Mole-Rats (Heterocephalus glaber)

“…PCTAIRE-3 is mainly expressed in differentiated neurones and has been linked to Alzheimer's disease pathology, both relating to amyloid precursor protein-dependent Alzheimer's pathology via phosphorylation [83] and by regulation of tau phosphorylation [84]. Multidrug resistance-associated protein 7 was identified in the hypoxia EV citrullinome; although deimination needs to be studied in this context, multidrug resistance is linked to hypoxia [85]. G-protein-coupled receptor 19 was identified in the EV citrullinome in hypoxia, and although effects of its deimination have not been reported, it has been linked to neonatal HI-induced brain damage [86].…”

Application of Metabolic Reprogramming to Cancer Imaging and Diagnosis

“…When 18 F-FMISO enters living cells, the nitro group of FMISO is reduced. In nonhypoxic cells, reduced FMISO molecules can be oxidized to diffuse into the free extracellular circulation and ultimately excreted [148][149][150]. However, in hypoxic tumor cells, this oxidation does not occur and the FMISO molecules accumulate.…”

Imaging of Tumor Hypoxia With Radionuclide-Labeled Tracers for PET

“…Another widely studied class of agents is the Cu complex with diacetyl-bis(N4-methylthiosemicarbazone) (ATSM) ligand, among which ATSM is the prototype (Figure 5). Fujibayashi [60][61][62][63][64] Cu isotope to label some compounds such as ATSM and used the synthesized 62 Cu-ATSM to study cardiac perfusion in a rat model. Their findings suggested that 62 Cu-ATSM could accumulate during hypoxia.…”

“…Fujibayashi [60][61][62][63][64] Cu isotope to label some compounds such as ATSM and used the synthesized 62 Cu-ATSM to study cardiac perfusion in a rat model. Their findings suggested that 62 Cu-ATSM could accumulate during hypoxia. Similarly, their studies on 64 Cu-ATSM, 18 F-FMISO, and 64 Cu-PTSM in EMT-6 tumor cells showed that 64 Cu-ATSM and 18 F-FMISO could differentially accumulate in tumors.…”

“…At the same time, the SUV mean ratio in tumors of mice in the treatment group is significantly higher than that of control mice in vivo PET studies. Therefore, it was found that MRP1 inhibitors can increase the accumulation of 18 F-FMISO in hypoxic cells (62). In other words, during this type of chemotherapy, it may lead to an overestimation of tumor hypoxia.…”