A Possible Explanation for a Neurotoxic Effect of the Anticancer Agent Oxaliplatin on Neuronal Voltage-Gated Sodium Channels

Abstract

Oxaliplatin, a new widely used anticancer drug, displays frequent, sometimes severe, acute sensory neurotoxicity accompanied by neuromuscular signs that look like the symptoms observed in tetany and myotonia. The whole cell patch-clamp technique was employed to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median (DUM) neurons isolated from the CNS of the cockroach Periplaneta americana. Within the clinical concentration range, oxaliplatin (40-500 microM), applied intracellularly, decreased the amplitude of the voltage-gated sodium current resulting in a reduction of half the amplitude of the action potential. For comparison, two other platinum derivatives, cisplatin and carboplatin, were found to be ineffective at reducing the sodium current amplitude. In addition, we compared the oxaliplatin action to those of its metabolites dichloro-diaminocyclohexane platinum (dach-Cl(2)-platin) and oxalate. Oxalate (500 microM) was found to be effective, like oxaliplatin, at reducing the inward sodium current amplitude, whereas dach-Cl(2)-platin (500 microM) failed to change the current amplitude. Interestingly, the effect of oxalate or oxaliplatin could be mimicked by using intracellularly applied 10 mM bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA), known as chelator of calcium ions. We concluded that oxaliplatin was capable of altering the voltage-gated sodium channels through a pathway involving calcium ions probably immobilized by its metabolite oxalate. The medical interest of preventing acute neurotoxic side effects of oxaliplatin by infusing Ca(2+) and Mg(2+) is discussed.

Oxaliplatin: A Review in the Era of Molecularly Targeted Therapy

“…Experimental data suggest that oxaliplatin affects voltage-gated sodium channels in complex pathways involving calcium. Calcium itself is chelated by oxalate, a metabolite of oxaliplatin 25 .…”

Chemotherapy-induced peripheral neuropathy: review for clinical practice

“…In this group of drugs, oxaliplatin may induce two types of neuropathy: one acute and reversible and the other chronic. Acute neuropathy seems to be caused by oxalate release, which is able to kelate extracellular calcium, interfering with sensory neurons depolarization with consequent membrane hyper-excitability 6 . Chronic neuropathy has several hypotheses for its development, including the fact that repeated acute neuropathy episodes may lead to chronic neural injuries.…”

Histological and biochemical studies on the effect of tetrodotoxin extracted from Puffer fish (Lagocephalus sceleratus) against carbon tetrachloride induced hepatotoxicity in albino mice.

“…This action, in return, prevents the carcinoma cells from getting enough Na + ions needed for their various intracellular functions, and above all to maintain the normal distribution of charge across the cell membrane, a process necessary to maintain cell integrity. Consequently, the proliferation and invasiveness of such cells are suppressed (Grolleau et al 2001;Bragadeeswaran et al, 2010).…”