MR. YAODONG YI

L002 Reduces Oxaliplatin Accumulation in the Dorsal Root Ganglion and Mitochondria Through Selectively Inhibiting the Transporter-Mediated Uptake Thereby Attenuates Peripheral Neurotoxicity

Oxaliplatin (OXA) is a third-generation platinum drug; however, severe peripheral neurotoxicity limits its application. This study aims to elucidate the transporter mechanisms of OXA and to explore whether L-tetrahydropalmatine (L-THP) would alleviate OXA-induced peripheral neurotoxicity by selectively inhibiting these uptake transporters in vitro and in vivo. Our results revealed that organic cation transporter 2 (OCT2), organic cation/carnitine transporter 1 (OCTN1) and organic cation/carnitine transporter 2 (OCTN2) were involved in uptake of DOX in dorsal root ganglion (DRG) neurons and mitochondria, respectively. L002 (1-100 μM) reduced OXA (40 μM) induced cytotoxicity in MDCK-hOCT2 (Madin–Darby canine kidney, MDCK), MDCK-hOCTN1, MDCK-hOCTN2, and rat primary DRG cells, and decreased the accumulation of OXA in above cells and rat DRG mitochondria, but did not affect its efflux from MDCK-hMRP2 cells. Furthermore, L002 (5-20 mg/kg for mice, 10-40 mg/kg for rats; twice a week) attenuated OXA (8 mg/kg for mice, 4 mg/kg for rats; twice a week) induced peripheral neurotoxicity and reduced the platinum concentration of the DRG. Whereas, L002 (1-100 μM for cells; 10-20 mg/kg for mice) did not impair the antitumour efficacy of OXA (40 μM for cells; 8 mg/kg for mice) in HT29 tumour-bearing nude mice nor in tumour cells (HT29 and SW620 cells). In conclusion, OCT2, OCTN1 and OCTN2 contribute to OXA uptake in the DRG and mitochondria. L-THP attenuates OXA-induced peripheral neurotoxicity via inhibiting OXA uptake but without impairing the antitumour efficacy of OXA. L002 is a potential candidate drug to attenuate OXA-induced peripheral neurotoxicity.