Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin
Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly...
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/14/11486 |
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| author | Anna Hucke Rita Schröter Cecilia Ceresa Alessia Chiorazzi Annalisa Canta Sara Semperboni Paola Marmiroli Guido Cavaletti Burkhard Gess Giuliano Ciarimboli |
| author_facet | Anna Hucke Rita Schröter Cecilia Ceresa Alessia Chiorazzi Annalisa Canta Sara Semperboni Paola Marmiroli Guido Cavaletti Burkhard Gess Giuliano Ciarimboli |
| author_sort | Anna Hucke |
| collection | DOAJ |
| description | Cisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2<sup>−/−</sup> mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2<sup>−/−</sup> mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2<sup>−/−</sup> mice). Comparing the apparent affinities (IC<sub>50</sub>) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC<sub>50</sub>: 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP. |
| first_indexed | 2024-03-11T01:00:54Z |
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| language | English |
| last_indexed | 2024-03-11T01:00:54Z |
| publishDate | 2023-07-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a6fe39dfd8d34ed4bfe87cbbee5411302023-11-18T19:40:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124141148610.3390/ijms241411486Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with CisplatinAnna Hucke0Rita Schröter1Cecilia Ceresa2Alessia Chiorazzi3Annalisa Canta4Sara Semperboni5Paola Marmiroli6Guido Cavaletti7Burkhard Gess8Giuliano Ciarimboli9Experimentelle Nephrologie, Medizinische Klinik D, Universitätsklinikum Münster, 48149 Münster, GermanyExperimentelle Nephrologie, Medizinische Klinik D, Universitätsklinikum Münster, 48149 Münster, GermanyExperimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, ItalyExperimental Neurology Unit, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, ItalyDepartment of Neurology, University Hospital Münster, 48149 Münster, GermanyExperimentelle Nephrologie, Medizinische Klinik D, Universitätsklinikum Münster, 48149 Münster, GermanyCisplatin (CDDP) is an efficient chemotherapeutic agent broadly used to treat solid cancers. Chemotherapy with CDDP can cause significant unwanted side effects such as renal toxicity and peripheral neurotoxicity. CDDP is a substrate of organic cation transporters (OCT), transporters that are highly expressed in renal tissue. Therefore, CDDP uptake by OCT may play a role in causing unwanted toxicities of CDDP anticancer treatment. In this study, the contribution of the mouse OCT2 (mOCT2) to CDDP nephro- and peripheral neurotoxicity was investigated by comparing the effects of cyclic treatment with low doses of CDDP on renal and neurological functions in wild-type (WT) mice and mice with genetic deletion of OCT2 (OCT2<sup>−/−</sup> mice). This CDDP treatment protocol caused significant impairment of kidneys and peripherical neurological functions in WT mice. These effects were significantly reduced in OCT2<sup>−/−</sup> mice, however, less profoundly than what was previously measured in mice with genetic deletion of both OCT1 and 2 (OCT1-2<sup>−/−</sup> mice). Comparing the apparent affinities (IC<sub>50</sub>) of mOCT1 and mOCT2 for CDDP, the mOCT1 displayed a higher affinity for CDDP than the mOCT2 (IC<sub>50</sub>: 9 and 558 µM, respectively). Also, cellular toxicity induced by incubation with 100 µM CDDP was more pronounced in cells stably expressing mOCT1 than in cells expressing mOCT2. Therefore, in mice, CDDP uptake by both OCT1 and 2 contributes to the development of CDDP undesired side effects. OCT seem to be suitable targets for establishing treatment protocols aimed at decreasing unwanted CDDP toxicity and improving anticancer treatment with CDDP.https://www.mdpi.com/1422-0067/24/14/11486transporterscisplatintoxicitykidneysdorsal root gangliaperipheral neurotoxicity |
| spellingShingle | Anna Hucke Rita Schröter Cecilia Ceresa Alessia Chiorazzi Annalisa Canta Sara Semperboni Paola Marmiroli Guido Cavaletti Burkhard Gess Giuliano Ciarimboli Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin International Journal of Molecular Sciences transporters cisplatin toxicity kidneys dorsal root ganglia peripheral neurotoxicity |
| title | Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin |
| title_full | Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin |
| title_fullStr | Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin |
| title_full_unstemmed | Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin |
| title_short | Role of Mouse Organic Cation Transporter 2 for Nephro- and Peripheral Neurotoxicity Induced by Chemotherapeutic Treatment with Cisplatin |
| title_sort | role of mouse organic cation transporter 2 for nephro and peripheral neurotoxicity induced by chemotherapeutic treatment with cisplatin |
| topic | transporters cisplatin toxicity kidneys dorsal root ganglia peripheral neurotoxicity |
| url | https://www.mdpi.com/1422-0067/24/14/11486 |
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