Interaction of Masitinib with Organic Cation Transporters
Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they...
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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/14189 |
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| author | Saliha Harrach Jasmin Haag Martin Steinbüchel Rita Schröter Ute Neugebauer Jessica Bertrand Giuliano Ciarimboli |
| author_facet | Saliha Harrach Jasmin Haag Martin Steinbüchel Rita Schröter Ute Neugebauer Jessica Bertrand Giuliano Ciarimboli |
| author_sort | Saliha Harrach |
| collection | DOAJ |
| description | Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they are hydrophilic and not able to cross cell membranes freely. Accordingly, the efficacy of TKI in target cells is closely dependent on the expression of their transporters. Specifically, Masitinib is an organic cation and is expected to interact with organic cation transporters (OCT and Multidrug and Toxin Extrusion proteins—MATE-). The aim of this work was to characterize the interaction of Masitinib with different OCTs. Human embryonic kidney 293 cells stably transfected with murine or human OCT were used for the experiments. The interaction of Masitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of this drug was quantified using high performance liquid chromatography. Our results identified interactions of Masitinib with almost all investigated mouse (m) and human (h) OCTs and hMATE1 and indicated OCT1 and hOCT2 to be especially potent Masitinib translocators across cell membranes. Interestingly, some important differences were observed for the interaction with murine and human OCTs. In the future, investigations concerning further in vitro and in vivo properties of Masitinib and its efficacy related to transporter-related uptake mechanisms under pathophysiological conditions should be performed. Clinical trials in humans and other animals with Masitinib have already shown promising results. However, further research is necessary to understand the disease specific transport mechanisms of Masitinib to contribute to a successful and responsible therapy employment. |
| first_indexed | 2024-03-09T18:17:08Z |
| format | Article |
| id | doaj.art-e3347118d39340f48ce8445fc9933cb7 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:17:08Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e3347118d39340f48ce8445fc9933cb72023-11-24T08:40:03ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221418910.3390/ijms232214189Interaction of Masitinib with Organic Cation TransportersSaliha Harrach0Jasmin Haag1Martin Steinbüchel2Rita Schröter3Ute Neugebauer4Jessica Bertrand5Giuliano Ciarimboli6Experimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, GermanyExperimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, GermanyExperimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, GermanyExperimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, GermanyExperimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, GermanyExperimental Orthopaedics, University Orthopaedic Clinic, Medical Faculty, University Hospital Magdeburg, 39120 Magdeburg, GermanyExperimental Nephrology, Department of Internal Medicine D, University Hospital Münster, 48149 Münster, GermanyTyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they are hydrophilic and not able to cross cell membranes freely. Accordingly, the efficacy of TKI in target cells is closely dependent on the expression of their transporters. Specifically, Masitinib is an organic cation and is expected to interact with organic cation transporters (OCT and Multidrug and Toxin Extrusion proteins—MATE-). The aim of this work was to characterize the interaction of Masitinib with different OCTs. Human embryonic kidney 293 cells stably transfected with murine or human OCT were used for the experiments. The interaction of Masitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of this drug was quantified using high performance liquid chromatography. Our results identified interactions of Masitinib with almost all investigated mouse (m) and human (h) OCTs and hMATE1 and indicated OCT1 and hOCT2 to be especially potent Masitinib translocators across cell membranes. Interestingly, some important differences were observed for the interaction with murine and human OCTs. In the future, investigations concerning further in vitro and in vivo properties of Masitinib and its efficacy related to transporter-related uptake mechanisms under pathophysiological conditions should be performed. Clinical trials in humans and other animals with Masitinib have already shown promising results. However, further research is necessary to understand the disease specific transport mechanisms of Masitinib to contribute to a successful and responsible therapy employment.https://www.mdpi.com/1422-0067/23/22/14189Masitinibtyrosine kinase inhibitorstransportorganic cation transporterrepurposing |
| spellingShingle | Saliha Harrach Jasmin Haag Martin Steinbüchel Rita Schröter Ute Neugebauer Jessica Bertrand Giuliano Ciarimboli Interaction of Masitinib with Organic Cation Transporters International Journal of Molecular Sciences Masitinib tyrosine kinase inhibitors transport organic cation transporter repurposing |
| title | Interaction of Masitinib with Organic Cation Transporters |
| title_full | Interaction of Masitinib with Organic Cation Transporters |
| title_fullStr | Interaction of Masitinib with Organic Cation Transporters |
| title_full_unstemmed | Interaction of Masitinib with Organic Cation Transporters |
| title_short | Interaction of Masitinib with Organic Cation Transporters |
| title_sort | interaction of masitinib with organic cation transporters |
| topic | Masitinib tyrosine kinase inhibitors transport organic cation transporter repurposing |
| url | https://www.mdpi.com/1422-0067/23/22/14189 |
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