The mechanism of the actions of oxaliplatin on ion currents and action potentials in differentiated NG108-15 neuronal cells.
Oxaliplatin (OXAL) is a platinum-based chemotherapeutic agent which is effective against advanced or metastatic gastrointestinal cancer. However, the mechanisms responsible for the development of the neuropathy induced by this agent remain unclear. In this study, we attempted to evaluate the possible effects of OXAL on ion currents and action potentials (APs) in NG108-15 cells differentiated with dibutyryl cyclic-AMP. Application of OXAL decreased the peak amplitude of voltage-gated Na(+) current (I(Na)) with no change in the overall current-voltage relations of the currents. This agent also produced a concentration-dependent slowing of I(Na) inactivation. A further application of ranolazine reversed OXAL-induced slowing of I(Na) inactivation. Unlike ranolazine or riluzole, OXAL had no effect on persistent I(Na) elicited by long ramp pulses. OXAL (100 microM) also had little or no effect on the peak amplitude of L-type Ca(2+) currents in NG108-15 cells, while it suppressed delayed-rectifier K(+) current. In current-clamp recordings, OXAL alone reduced the amplitude of APs; however, it did not alter the duration of APs. However, after application of tefluthrin, OXAL did increase the duration of APs. Moreover, OXAL decreased the peak amplitude of I(Na) with a concomitant reduction of current inactivation in HEK293T cells expressing SCN5A. The effects of OXAL on ion currents presented here may contribute to its neurotoxic actions in vivo.
Wu
Sheng-Nan
SN
Department of Physiology, National Cheng Kung University Medical College, No. 1, University Road, Tainan 70101, Taiwan. snwu@mail.ncku.edu.tw
Chen
Bing-Shuo
BS
Wu
Yung-Han
YH
Peng
Hsung
H
Chen
Li-Tzong
LT
D000200:Action Potentials / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D003521:Cyclopropanes / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D016014:Linear Models; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014162:Transfection
D000970:Antineoplastic Agents; D003521:Cyclopropanes; D006845:Hydrocarbons, Fluorinated; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009944:Organoplatinum Compounds; D026902:Potassium Channel Blockers; C568320:SCN5A protein, human; C568322:Scn5a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000077150:Oxaliplatin; C489827:2,3,5,6-tetrafluoro-4-methylbenzyl (Z)-(1RS)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate; D013779:Tetrodotoxin; D003994:Bucladesine; D019789:Tetraethylammonium