Indole-3-carbinol is an inhibitor of KV1.3 potassium voltage-gated channel activity in chronic lymphocytic leukemia cells

Potassium voltage-gated channels are attractive drug targets for cancer treatment. In this report, we show that K_V1.3 current amplitude is greater in CLL cells from refractory patients compared to CLL cells from untreated patients, further supporting a role for Kv1.3 channel as a target for refractory CLL disease. Indole-3 carbinol (I3C) is a clinically tested natural product found in edible Brassica plants. Here we show that I3C inhibits K_V1.3 currents in transfected HEK293 (43.9 ± 7.6 %; 50 μM I3C), Burkitt's lymphoma BL60.2 (52.2 ± 5.2 %; 10 μM) and chronic lymphocytic leukemia (CLL) (57.7 % ± 5.2; 10 μM) cells. I3C inhibition was concentration-dependent in HEK293 (IC₅₀ = 54 μM; n_H = 3.2), BL60.2 (IC₅₀ = 1.06 μM; n_H = 0.53) and CLL (IC₅₀ = 5.2 μM; n_H = 0.95) cells, and the effect on K_V1.3 was produced in a voltage-, time- and use-dependent manner, consistent with an open state blockade mechanism. I3C also inhibited K_V11.1 currents, but failed to inhibit other K_V channels and K_ca3.1. Interestingly I3C did not induce mitochondrial depolarization of CLL cells, suggesting that I3C only targets plasma, but not mitochondria, Kv1.3 channels. I3C and derivatives 6-methyl-I3C and 3,3'-diindolylmethane, but no other indoles, that we previously showed induced apoptosis in Burkitt's and CLL cells, also efficiently inhibited K_V1.3 currents. However, I3C-mediated K_V1.3 currents inhibition was observed in CLL cells irrespective of their sensitivity to I3C-induced cell death, thus indicating that plasma membrane K_V1.3 inhibition is not sufficient to induce CLL cell death.