Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake
Ines Klein,
Jörg Isensee,
Martin H. J. Wiesen,
Thomas Imhof,
Meike K. Wassermann,
Carsten Müller,
Tim Hucho,
Manuel Koch,
Helmar C. Lehmann
Affiliations
Ines Klein
Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Jörg Isensee
Translational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Martin H. J. Wiesen
Pharmacology at the Laboratory Diagnostics Center, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Thomas Imhof
Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Meike K. Wassermann
Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Carsten Müller
Pharmacology at the Laboratory Diagnostics Center, Therapeutic Drug Monitoring, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Tim Hucho
Translational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Manuel Koch
Center for Biochemistry, Institute for Dental Research and Oral Musculoskeletal Research, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
Helmar C. Lehmann
Department of Neurology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany
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.
