Polymorphism of CAG motif of SK3 gene is associated with acute oxaliplatin neurotoxicity

Abstract

Purpose. There is no agreement on which channel is involved in oxaliplatin neurotoxicity, most investigators favouring voltage-gated sodium channels. However, the small conductance Ca ++ activated K + channels, encoded by the SK 1-3 genes, are also involved in membrane excitability, playing a role in after-hyperpolarisation at the motor nerve terminal. As the SK3 gene is characterised in Caucasians by a highly polymorphic CAG motif within the exon 1, we hypothesise that SK3 gene polymorphism may influence the development of acute nerve hyperexcitability in oxaliplatin-treated patients. Methods.Patients eligible for an oxaliplatin-containing regimen were enrolled. Detailed neurological examination, nerve conduction studies and needle electromyography were performed before and after oxaliplatin administration. DNA was extracted by polymerase chain reaction and each allele was isolated and sequenced.Results. We evaluated 40 patients. After oxaliplatin administration, 28 patients developed symptoms of neurotoxicity, which were severe in eleven. Patients were divided into 3 groups according to neurophysiologic data : G0 (normal peripheral nerve excitability [PNE]), 16 patients; G1 (mild PNE), 15 patients; G2 (severe PNE), 9 patients. Genetic analysis showed different alleles ranging from 13 to 23 CAG repeats. Patients carrying alleles containing 13-15 CAG repeats experienced a significantly higher incidence of severe nerve hyperexcitability (chi-square 48.6; df 16; p = .0001). Conclusion.The results suggest that OXA-neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarisation. The 13-14 CAG repeat allele could mark patients susceptible to acute OXA neurotoxicity.3

Ion channels and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy

“…79 K Ca 2.3 is responsible for the AP AHP, thereby helping control neuronal excitability, and is located both in the spinal cord and in DRGs. 114 K Ca 2.3 channels have a CAG motif that can repeat between 12 and 26 times 115 and is essential for channel tetramerization.…”

Targeting SKCa Channels in Cancer: Potential New Therapeutic Approaches

“…Indeed, clinical and electrophysiological studies have shown that oxaliplatin leads to the hyperexcitability of peripheral motor nerves, in which the SK3 channel is strongly expressed. An inverse linear relationship between the number of CAG repeats and the occurrence of toxicity, with lower numbers of CAG motifs correlating with more frequent acute neurotoxicity, has been observed [24].…”

“…NS8593 (24) (Fig. 6) was the first KCa inhibitor to be identified that acts by decreasing the Ca 2+ sensitivity of KCa channels [127].…”

“…The SK3 channel is strongly expressed in peripheral motor nerves and it has recently been shown that oxaliplatin neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene (see paragraph 1.3.2 SK3 variants part). The 13-14 CAG repeat allele could be a promising prognostic marker of acute oxaliplatin neurotoxicity [24]. However, further studies are required to determine whether oxaliplatin directly acts in the function of SK3 channel in peripheral motor nerves.…”

Neuropathy Secondary to Chemotherapy: A Real Issue for Cancer Survivors

“…Because the SK3 gene is characterised in Caucasians by a highly polymorphic CAG motif within exon 1, SK3 gene polymorphism may influence the development of acute nerve hyperexcitability in oxaliplatin-treated patients. The results of the study by Basso et al (2011) have suggested that oxaliplatin neurotoxicity may be related to distribution of the polymorphic CAG motif of the SK3 gene, which might modulate nerve after-hyperpolarisation. The allele with 13-14 CAG repeats could mark patients susceptible to acute oxaliplatin neurotoxicity.…”