Glycyrrhizic Acid Prevents Paclitaxel-Induced Neuropathy via Inhibition of OATP-Mediated Neuronal Uptake

Area of Science:

• Neuroscience
• Pharmacology
• Oncology

Background:

• Paclitaxel is a vital chemotherapy drug.
• Peripheral neuropathy is a common, dose-limiting side effect of paclitaxel treatment.
• The precise mechanisms of paclitaxel entry into neurons remain unclear.

Purpose of the Study:

• To elucidate the neuronal uptake mechanisms of paclitaxel.
• To identify specific drug transporters responsible for paclitaxel neurotoxicity.
• To explore strategies for preventing paclitaxel-induced peripheral neuropathy.

Main Methods:

• Utilized inhibitors of endocytosis, autophagy, and organic anion-transporting polypeptides (OATPs).
• Investigated paclitaxel transport using drug derivatives and OATP modulation (overexpression, CRISPR/Cas9-knock-out).
• Quantified OATP expression via RT-qPCR in neuronal tissues and cell lines.

Main Results:

• Identified OATP1A1 and OATP1B2 as the primary neuronal transporters for paclitaxel.
• Inhibition of OATP1A1 and OATP1B2 by glycyrrhizic acid reduced neurotoxicity in vitro and in vivo.
• Paclitaxel's anti-cancer efficacy was preserved when OATPs were inhibited.

Conclusions:

• Organic anion-transporting polypeptides (OATPs) mediate paclitaxel transport into neurons.
• Targeting OATP1A1 and OATP1B2 represents a potential therapeutic strategy to mitigate paclitaxel-induced peripheral neuropathy.
• This finding offers a novel approach to improve chemotherapy tolerability.