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Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors
BACKGROUND: [(18)F]Fluoromisonidazole ([(18)F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [(18)F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [(18)F]FMISO uptake level va...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Springer Berlin Heidelberg
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835267/ https://www.ncbi.nlm.nih.gov/pubmed/33492449 http://dx.doi.org/10.1186/s13550-021-00752-3 |
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author | Shimizu, Yoichi Nakai, Yukihiro Watanabe, Hiroyuki Iikuni, Shimpei Ono, Masahiro Saji, Hideo Kuge, Yuji Saga, Tsuneo Nakamoto, Yuji |
author_facet | Shimizu, Yoichi Nakai, Yukihiro Watanabe, Hiroyuki Iikuni, Shimpei Ono, Masahiro Saji, Hideo Kuge, Yuji Saga, Tsuneo Nakamoto, Yuji |
author_sort | Shimizu, Yoichi |
collection | PubMed |
description | BACKGROUND: [(18)F]Fluoromisonidazole ([(18)F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [(18)F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [(18)F]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 [(18)F]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 [(18)F]FMISO for 4 h under hypoxia, and their radioactivity was then measured. FaDu tumor-bearing mice were intravenously injected with [(18)F]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 SUV(mean) 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 [(18)F]FMISO accumulation in hypoxic cells. This suggests that [(18)F]FMISO-PET imaging is affected by MRP1 inhibitors independent of the hypoxic state. |
format | Online Article Text |
id | pubmed-7835267 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-78352672021-01-29 Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors Shimizu, Yoichi Nakai, Yukihiro Watanabe, Hiroyuki Iikuni, Shimpei Ono, Masahiro Saji, Hideo Kuge, Yuji Saga, Tsuneo Nakamoto, Yuji EJNMMI Res Preliminary Research BACKGROUND: [(18)F]Fluoromisonidazole ([(18)F]FMISO) is a PET imaging probe widely used for the detection of hypoxia. We previously reported that [(18)F]FMISO is metabolized to the glutathione conjugate of the reduced form in hypoxic cells. In addition, we found that the [(18)F]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 [(18)F]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 [(18)F]FMISO for 4 h under hypoxia, and their radioactivity was then measured. FaDu tumor-bearing mice were intravenously injected with [(18)F]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 SUV(mean) 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 [(18)F]FMISO accumulation in hypoxic cells. This suggests that [(18)F]FMISO-PET imaging is affected by MRP1 inhibitors independent of the hypoxic state. Springer Berlin Heidelberg 2021-01-25 /pmc/articles/PMC7835267/ /pubmed/33492449 http://dx.doi.org/10.1186/s13550-021-00752-3 Text en © The Author(s) 2021 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Preliminary Research Shimizu, Yoichi Nakai, Yukihiro Watanabe, Hiroyuki Iikuni, Shimpei Ono, Masahiro Saji, Hideo Kuge, Yuji Saga, Tsuneo Nakamoto, Yuji Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors |
title | Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors |
title_full | Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors |
title_fullStr | Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors |
title_full_unstemmed | Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors |
title_short | Increased [(18)F]FMISO accumulation under hypoxia by multidrug-resistant protein 1 inhibitors |
title_sort | increased [(18)f]fmiso accumulation under hypoxia by multidrug-resistant protein 1 inhibitors |
topic | Preliminary Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835267/ https://www.ncbi.nlm.nih.gov/pubmed/33492449 http://dx.doi.org/10.1186/s13550-021-00752-3 |
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