Inhibition of a Mitochondrial Potassium Channel as a New Therapeutic Strategy for Chronic Lymphocytic Leukemia

Abstract

Ion channels are involved in the regulation of proliferation and apoptosis and are emerging as promising oncological targets. We have recently identified three membrane-permeant inhibitors of the Kv1.3 potassium channel as inducers of apoptosis. These inhibitors induce mitochondrial membrane potential changes, increase of ROS release and opening of the permeability transition pore finally leading to cytochrome c release and cells death. Death occurs only when Kv1.3 is active in the inner mitochondrial membrane (mtKv1.3) and also in the absence of Bax and Bak. Efficiency of one of these inhibitors to reduce tumor volume in vivo was demonstrated in a melanoma orthotopic mouse model (Leanza, et al., 2012 EMBO Molecular Medicine). The same signaling pathway and a selective action of the Kv1.3 inhibitors was observed in B lymphocytes of patients suffering of Chronic lymphocytic leukemia (B-CLL) (Leanza, et al., 2013 Leukemia). Regarding the mechanism of selectivity, we defined that synergy between the level of Kv1.3 expression and an altered redox state in B-CLL cells determines the susceptibility of these cells. Since Kv1.3 inhibitors kill B-CLL by direct interference with mitochondrial functions, they act on these malignant cells independent of classic prognostic factors and Bcl-2 overexpression. To generalize our findings, in addition to melanoma and B-CLL cells, the effect of these inhibitors on cell survival was measured on different cancer cell lines expressing Kv1.3. A correlation between Kv1.3 expression and susceptibility to mtKv1.3 inhibitors was found.