Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations
Cancer treatment with platinum compounds is an important achievement of modern chemotherapy. However, despite the beneficial effects, the clinical impact of these agents is hampered by the development of drug resistance as well as dose-limiting side effects. The efficacy but also side effects of pla...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-05-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2018.00180/full |
| _version_ | 1828481797362548736 |
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| author | Anna Hucke Ga Young Park Oliver B. Bauer Georg Beyer Christina Köppen Dorothea Zeeh Christoph A. Wehe Michael Sperling Michael Sperling Rita Schröter Marta Kantauskaitè Yohannes Hagos Uwe Karst Stephen J. Lippard Giuliano Ciarimboli |
| author_facet | Anna Hucke Ga Young Park Oliver B. Bauer Georg Beyer Christina Köppen Dorothea Zeeh Christoph A. Wehe Michael Sperling Michael Sperling Rita Schröter Marta Kantauskaitè Yohannes Hagos Uwe Karst Stephen J. Lippard Giuliano Ciarimboli |
| author_sort | Anna Hucke |
| collection | DOAJ |
| description | Cancer treatment with platinum compounds is an important achievement of modern chemotherapy. However, despite the beneficial effects, the clinical impact of these agents is hampered by the development of drug resistance as well as dose-limiting side effects. The efficacy but also side effects of platinum complexes can be mediated by uptake through plasma membrane transporters. In the kidneys, plasma membrane transporters are involved in their secretion into the urine. Renal secretion is accomplished by uptake from the blood into the proximal tubules cells, followed by excretion into the urine. The uptake process is mediated mainly by organic cation transporters (OCT), which are expressed in the basolateral domain of the plasma membrane facing the blood. The excretion of platinum into the urine is mediated by exchange with protons via multidrug and toxin extrusion proteins (MATE) expressed in the apical domain of plasma membrane. Recently, the monofunctional, cationic platinum agent phenanthriplatin, which is able to escape common cellular resistance mechanisms, has been synthesized and investigated. In the present study, the interaction of phenanthriplatin with transporters for organic cations has been evaluated. Phenanthriplatin is a high affinity substrate for OCT2, but has a lower apparent affinity for MATEs. The presence of these transporters increased cytotoxicity of phenanthriplatin. Therefore, phenanthriplatin may be especially effective in the treatment of cancers that express OCTs, such as colon cancer cells. However, the interaction of phenanthriplatin with OCTs suggests that its use as chemotherapeutic agent may be complicated by OCT-mediated toxicity. Unlike cisplatin, phenanthriplatin interacts with high specificity with hMATE1 and hMATE2K in addition to hOCT2. This interaction may facilitate its efflux from the cells and thereby decrease overall efficacy and/or toxicity. |
| first_indexed | 2024-12-11T08:03:19Z |
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| id | doaj.art-a08b11d276134b76b82f7a8c9f729f2d |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-11T08:03:19Z |
| publishDate | 2018-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-a08b11d276134b76b82f7a8c9f729f2d2022-12-22T01:15:04ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462018-05-01610.3389/fchem.2018.00180360040Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic CationsAnna Hucke0Ga Young Park1Oliver B. Bauer2Georg Beyer3Christina Köppen4Dorothea Zeeh5Christoph A. Wehe6Michael Sperling7Michael Sperling8Rita Schröter9Marta Kantauskaitè10Yohannes Hagos11Uwe Karst12Stephen J. Lippard13Giuliano Ciarimboli14Experimental Nephrology, Medical Clinic D, University Hospital, University of Münster, Münster, GermanyDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United StatesInstitute of Inorganic and Analytical Chemistry, University of Münster, Münster, GermanyExperimental Nephrology, Medical Clinic D, University Hospital, University of Münster, Münster, GermanyInstitute of Inorganic and Analytical Chemistry, University of Münster, Münster, GermanyExperimental Nephrology, Medical Clinic D, University Hospital, University of Münster, Münster, GermanyInstitute of Inorganic and Analytical Chemistry, University of Münster, Münster, GermanyInstitute of Inorganic and Analytical Chemistry, University of Münster, Münster, GermanyEuropean Virtual Institute for Speciation Analysis, Münster, GermanyExperimental Nephrology, Medical Clinic D, University Hospital, University of Münster, Münster, GermanyExperimental Nephrology, Medical Clinic D, University Hospital, University of Münster, Münster, GermanyPortaCellTec Biosciences GmbH, Göttingen, GermanyInstitute of Inorganic and Analytical Chemistry, University of Münster, Münster, GermanyDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United StatesExperimental Nephrology, Medical Clinic D, University Hospital, University of Münster, Münster, GermanyCancer treatment with platinum compounds is an important achievement of modern chemotherapy. However, despite the beneficial effects, the clinical impact of these agents is hampered by the development of drug resistance as well as dose-limiting side effects. The efficacy but also side effects of platinum complexes can be mediated by uptake through plasma membrane transporters. In the kidneys, plasma membrane transporters are involved in their secretion into the urine. Renal secretion is accomplished by uptake from the blood into the proximal tubules cells, followed by excretion into the urine. The uptake process is mediated mainly by organic cation transporters (OCT), which are expressed in the basolateral domain of the plasma membrane facing the blood. The excretion of platinum into the urine is mediated by exchange with protons via multidrug and toxin extrusion proteins (MATE) expressed in the apical domain of plasma membrane. Recently, the monofunctional, cationic platinum agent phenanthriplatin, which is able to escape common cellular resistance mechanisms, has been synthesized and investigated. In the present study, the interaction of phenanthriplatin with transporters for organic cations has been evaluated. Phenanthriplatin is a high affinity substrate for OCT2, but has a lower apparent affinity for MATEs. The presence of these transporters increased cytotoxicity of phenanthriplatin. Therefore, phenanthriplatin may be especially effective in the treatment of cancers that express OCTs, such as colon cancer cells. However, the interaction of phenanthriplatin with OCTs suggests that its use as chemotherapeutic agent may be complicated by OCT-mediated toxicity. Unlike cisplatin, phenanthriplatin interacts with high specificity with hMATE1 and hMATE2K in addition to hOCT2. This interaction may facilitate its efflux from the cells and thereby decrease overall efficacy and/or toxicity.https://www.frontiersin.org/article/10.3389/fchem.2018.00180/fullorganic cation transportersplatinum compoundsinteractiontoxicityefficacyside effects |
| spellingShingle | Anna Hucke Ga Young Park Oliver B. Bauer Georg Beyer Christina Köppen Dorothea Zeeh Christoph A. Wehe Michael Sperling Michael Sperling Rita Schröter Marta Kantauskaitè Yohannes Hagos Uwe Karst Stephen J. Lippard Giuliano Ciarimboli Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations Frontiers in Chemistry organic cation transporters platinum compounds interaction toxicity efficacy side effects |
| title | Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations |
| title_full | Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations |
| title_fullStr | Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations |
| title_full_unstemmed | Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations |
| title_short | Interaction of the New Monofunctional Anticancer Agent Phenanthriplatin With Transporters for Organic Cations |
| title_sort | interaction of the new monofunctional anticancer agent phenanthriplatin with transporters for organic cations |
| topic | organic cation transporters platinum compounds interaction toxicity efficacy side effects |
| url | https://www.frontiersin.org/article/10.3389/fchem.2018.00180/full |
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