L-tetrahydropalmatine reduces oxaliplatin-induced neurotoxicity by selectively inhibiting the transporter-mediated uptake in the dorsal root ganglion

Abstract

Background and Purpose Oxaliplatin (OXA) is a third-generation anti-tumour platinum drug; however, the high accumulation of OXA in the dorsal root ganglia (DRG) induces severe peripheral neurotoxicity, which limits its application. This study aims to confirm the role of OCT2, OCTN1, and OCTN2 in the transcellular transport of OXA and to explore whether L-tetrahydropalmatine (L-THP) would selectively inhibit the uptake transporters and subsequently alleviate OXA-induced peripheral neurotoxicity. Experimental Approaches Transporter-transfected MDCK cells, primary DRG cells and tumour cell lines were utilized in vitro studies. OXA-induced chronic peripheral neurotoxicity mice and tumour-bearing nude mice were used in vivo studies. Key Results OCT2 and OCTN1 but not OCTN2 were involved in the uptake of OXA; OCT2 played the most important role. L-THP reduced the cytotoxicity and cellular accumulation of OXA in a concentration-dependent manner in MDCK-hOCT2, MDCK-hOCTN1, and rat primary DRG cells but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, L-THP attenuated OXA-induced peripheral neurotoxicity and reduced the platinum concentration in the DRG in mice in a dose-dependent manner. L-THP did not reduce the platinum concentration in the tumours and did not impair the antitumour efficacy of OXA in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). Conclusion and Implications OCT2 and OCTN1, especially OCT2, contribute to OXA uptake in the DRG. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OCT2 and OCTN1 but without impairing the antitumour efficacy of OXA. L-THP is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.