Volume-sensitive Cl- channel as a regulator of acquired cisplatin resistance

The platinum-based drug cisplatin (cis-diamminedichloroplatinum < II >) is widely used in cancer therapy. However, cancer cells can develop resistance after exposure to cisplatin. Recently, many studies have pointed to the involvement of plasma membrane ion channels in a cell's response to cisplatin. Our group has found that pretreatment with cisplatin enhanced the activity of volume-sensitive Cl- channels in human epidermoid cancer KB cells; cisplatin-resistant KCP-4 cells derived from KB cells, on the other hand, lacked functional expression of these channels. This suggests that the activity of volume-sensitive Cl- channels is an important factor in determining the sensitivity of cancer cells to cisplatin. Furthermore, when volume-sensitive Cl- channel function was partially restored in cisplatin-resistant KCP-4 cells treated with a histone deacetylase inhibitor, KCP-4 cells exhibited a restoration of sensitivity to cisplatin; this increased sensitivity was inhibited by a volume-sensitive Cl- channel blocker. We therefore propose that impaired activity of the volume-sensitive Cl- channel is involved in the acquired cisplatin resistance of these cancer cells. In this review, we will outline the relationship between volume-sensitive Cl- channels, cisplatin-induced apoptosis, and cisplatin resistance. Activating the volume-sensitive outwardly-rectifying Cl- channel may be a new strategy in treating clinical cisplatin resistance.