Although
chemotherapy is able to cure many patients with
malignancies, it still also often fails. Therefore, novel approaches and targets for chemotherapeutic treatment of
malignancies are urgently required. Recent studies demonstrated the expression of several
potassium channels in the inner mitochondrial membrane. Among them the
voltage gated potassium channel Kv1.3 and the big-
potassium (
BK) channel were shown to directly function in cell death by serving as target for pro-apoptotic Bax and Bak
proteins. Here, we discuss the role of mitochondrial
potassium channel Kv1.3 (mitoKv1.3) in cell death and its potential function in treatment of solid
tumors,
leukemia and
lymphoma. Bax and Bak inhibit mitoKv1.3 by directly binding into the pore of the channel, by a toxin-like mechanism. Inhibition of mitoKv1.3 results in an initial hyperpolarization of the inner mitochondrial membrane that triggers the production of
reactive oxygen species (ROS). ROS in turn induce a release of
cytochrome c from the cristae of the inner mitochondrial membrane and an activation of the permeability transition pore, resulting in opening of the intrinsic apoptotic cell death. Since mitoKv1.3 functions downstream of pro-apoptotic Bax and Bak, compounds that directly inhibit mitoKv1.3 may serve as a new class of drugs for treatment of
tumors, even with an altered expression of either pro- or anti-apoptotic Bcl-2
protein family members. This was successfully proven by the in vivo treatment of mouse
melanoma and ex vivo human chronic
leukemia B cells with inhibitors of mitoKv1.3.