Oxaliplatin neurotoxicity--no general ion channel surface-charge effect.
BACKGROUND
Oxaliplatin is a platinum-based chemotherapeutic drug. Neurotoxicity is the dose-limiting side effect. Previous investigations have reported that acute neurotoxicity could be mediated via voltage-gated ion channels. A possible mechanism for some of the effects is a modification of surface charges around the ion channel, either because of chelation of extracellular Ca2+, or because of binding of a charged biotransformation product of oxaliplatin to the channel. To elucidate the molecular mechanism, we investigated the effects of oxaliplatin and its chloride complex [Pt(dach)oxCl](-) on the voltage-gated Shaker K channel expressed in Xenopus oocytes. The recordings were made with the two-electrode and the cut-open oocyte voltage clamp techniques.


CONCLUSIONS
To our surprise, we did not see any effects on the current amplitudes, on the current time courses, or on the voltage dependence of the Shaker wild-type channel. Oxaliplatin is expected to bind to cysteines. Therefore, we explored if there could be a specific effect on single (E418C) and double-cysteine (R362C/F416C) mutated Shaker channels previously shown to be sensitive to cysteine-specific reagents. Neither of these channels were affected by oxaliplatin. The clear lack of effect on the Shaker K channel suggests that oxaliplatin or its monochloro complex has no general surface-charge effect on the channels, as has been suggested before, but rather a specific effect to the channels previously shown to be affected.
Broomand
Amir
A
Department of Oncology-Pathology, Karolinska Institutet and Karolinska Pharmacy, Karolinska University Hospital, Solna, Stockholm, Sweden. amibr@ibk.liu.se
Jerremalm
Elin
E
Yachnin
Jeffrey
J
Ehrsson
Hans
H
Elinder
Fredrik
F
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000378:metabolism
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D051637:Shaker Superfamily of Potassium Channels; D000077150:Oxaliplatin; D003545:Cysteine