Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake
Peripheral neuropathy is a common side effect of cancer treatment with paclitaxel. The mechanisms by which paclitaxel is transported into neurons, which are essential for preventing neuropathy, are not well understood. We studied the uptake mechanisms of paclitaxel into neurons using inhibitors for...
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2023-04-01
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| author | Ines Klein Jörg Isensee Martin H. J. Wiesen Thomas Imhof Meike K. Wassermann Carsten Müller Tim Hucho Manuel Koch Helmar C. Lehmann |
| author_facet | Ines Klein Jörg Isensee Martin H. J. Wiesen Thomas Imhof Meike K. Wassermann Carsten Müller Tim Hucho Manuel Koch Helmar C. Lehmann |
| author_sort | Ines Klein |
| collection | DOAJ |
| description | Peripheral neuropathy is a common side effect of cancer treatment with paclitaxel. The mechanisms by which paclitaxel is transported into neurons, which are essential for preventing neuropathy, are not well understood. We studied the uptake mechanisms of paclitaxel into neurons using inhibitors for endocytosis, autophagy, organic anion-transporting polypeptide (OATP) drug transporters, and derivatives of paclitaxel. RT-qPCR was used to investigate the expression levels of OATPs in different neuronal tissues and cell lines. OATP transporters were pharmacologically inhibited or modulated by overexpression and CRISPR/Cas9-knock-out to investigate paclitaxel transport in neurons. Through these experiments, we identified OATP1A1 and OATP1B2 as the primary neuronal transporters for paclitaxel. In vitro inhibition of OATP1A1 and OAT1B2 by glycyrrhizic acid attenuated neurotoxicity, while paclitaxel’s antineoplastic effects were sustained in cancer cell lines. In vivo, glycyrrhizic acid prevented paclitaxel-induced toxicity and improved behavioral and electrophysiological measures. This study indicates that a set of OATPs are involved in paclitaxel transport into neurons. The inhibition of OATP1A1 and OATP1B2 holds a promising strategy to prevent paclitaxel-induced peripheral neuropathy. |
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| last_indexed | 2024-03-11T04:22:42Z |
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| spelling | doaj.art-ea8159b8f82d4bff9777993fe6df54a12023-11-17T22:43:20ZengMDPI AGCells2073-44092023-04-01129124910.3390/cells12091249Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal UptakeInes Klein0Jörg Isensee1Martin H. J. Wiesen2Thomas Imhof3Meike K. Wassermann4Carsten Müller5Tim Hucho6Manuel Koch7Helmar C. Lehmann8Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyTranslational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyPharmacology at the Laboratory Diagnostics Center, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyCenter for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyDepartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyPharmacology at the Laboratory Diagnostics Center, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyTranslational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyCenter for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyDepartment of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, GermanyPeripheral neuropathy is a common side effect of cancer treatment with paclitaxel. The mechanisms by which paclitaxel is transported into neurons, which are essential for preventing neuropathy, are not well understood. We studied the uptake mechanisms of paclitaxel into neurons using inhibitors for endocytosis, autophagy, organic anion-transporting polypeptide (OATP) drug transporters, and derivatives of paclitaxel. RT-qPCR was used to investigate the expression levels of OATPs in different neuronal tissues and cell lines. OATP transporters were pharmacologically inhibited or modulated by overexpression and CRISPR/Cas9-knock-out to investigate paclitaxel transport in neurons. Through these experiments, we identified OATP1A1 and OATP1B2 as the primary neuronal transporters for paclitaxel. In vitro inhibition of OATP1A1 and OAT1B2 by glycyrrhizic acid attenuated neurotoxicity, while paclitaxel’s antineoplastic effects were sustained in cancer cell lines. In vivo, glycyrrhizic acid prevented paclitaxel-induced toxicity and improved behavioral and electrophysiological measures. This study indicates that a set of OATPs are involved in paclitaxel transport into neurons. The inhibition of OATP1A1 and OATP1B2 holds a promising strategy to prevent paclitaxel-induced peripheral neuropathy.https://www.mdpi.com/2073-4409/12/9/1249paclitaxeltaxolCIPNOATPOATP1B2OATP1A1 |
| spellingShingle | Ines Klein Jörg Isensee Martin H. J. Wiesen Thomas Imhof Meike K. Wassermann Carsten Müller Tim Hucho Manuel Koch Helmar C. Lehmann Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake Cells paclitaxel taxol CIPN OATP OATP1B2 OATP1A1 |
| title | Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake |
| title_full | Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake |
| title_fullStr | Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake |
| title_full_unstemmed | Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake |
| title_short | Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake |
| title_sort | glycyrrhizic acid prevents paclitaxel induced neuropathy via inhibition of oatp mediated neuronal uptake |
| topic | paclitaxel taxol CIPN OATP OATP1B2 OATP1A1 |
| url | https://www.mdpi.com/2073-4409/12/9/1249 |
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