Potassium voltage-gated channels are attractive drug targets for cancer treatment. In this report, we show that KV1.3 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 KV1.3 currents in transfected HEK293 (43.9 +/- 7.6 %; 50 mu M I3C), Burkitt's lymphoma BL60.2 (52.2 +/- 5.2 %; 10 mu M) and chronic lymphocytic leukemia (CLL) (57.7 % +/- 5.2; 10 mu M) cells. I3C inhibition was concentrationdependent in HEK293 (IC50 = 54 mu M; nH = 3.2), BL60.2 (IC50 = 1.06 mu M; nH = 0.53) and CLL (IC50 = 5.2 mu M; nH = 0.95) cells, and the effect on KV1.3 was produced in a voltage-, time- and use-dependent manner, consistent with an open state blockade mechanism. I3C also inhibited KV11.1 currents, but failed to inhibit other KV channels and Kca3.1. 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 KV1.3 currents. However, I3C-mediated KV1.3 currents inhibition was observed in CLL cells irrespective of their sensitivity to I3C-induced cell death, thus indicating that plasma membrane KV1.3 inhibition is not sufficient to induce CLL cell death.