P0111 Voltage-gated K+ channels as potential therapeutic targets for lung cancer therapy

Abstract

Background Voltage-gated K + (kV) channels are considered to be a regulator of membrane potential and cell excitability. Recently, evidence has indicated that several kV channel subtypes contribute to the control of cell proliferation in various types of cancer cells and are worthy of investigation as molecular targets for cancer therapy. Methods We investigated the effects of the dendrotoxin-κ (DTX-κ) and margatoxin (MgTX) which are Kv1.1 and Kv1.3 specific blockers, respectively, on tumour formation using a xenograft model induced by A549 and H460 cells. Findings The mRNA and protein of Kv1.1 and Kv1.3 was expressed in A549 and H460 cells and the blockade of Kv1.1 by DTX-κ or Kv1.3 by MgTX reduced the formation of tumours in nude mice. Furthermore, treatment with DTX-κ significantly increased the protein expression of p21 Waf 1/ Cip 1 , p27 Kip 1 , and p15 INK 4 B , and significantly decreased the protein expression of cyclin D3 in tumour tissues compared to control. In addition, selective inhibition of Kv1.3 significantly increased expression level of p21 Waf 1/ Cip 1 and significantly decreased the expression level of Cdk4 and cyclin D3. Moreover, we found that the effect of DTX- κ and gefitinib was synergistic in H460 and A549 cells. Interpretation These results suggest that certain kV channels may serve as novel therapeutic targets for lung cancer therapy and could be one of multiple molecular targets to overcome tyrosine kinase inhibitor resistance. This work is supported by National Research Foundation of Korea (2012R1A2A2A01047151).