Targeting mitochondrial ion channels for cancer therapy

Abstract

Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

Keywords: Cancer; Channel interactions; Drug targeting; Ion channels; Mitochondria.

Fig. 1

Role of the mitochondrial permeability transition pore (MPTP) and its activators in cell death. MPTP can be activated indirectly by different drugs (only those exerting a beneficial effect against cancer in vivo are indicated in the box) eliciting changes in inner membrane potential or causing ROS production or leading to calcium overload in the matrix. MPTP opening leads to swelling, rupture of MOM that contributes to cytochrome c release, a process required for apoptosome formation and subsequent activation of effector caspases. See text (par. 2.1) for further details.

Fig. 2

Role oftheVoltage-dependent anion channels (VDAC) andtheirpharmacological modulation in cell death. Decrease of the conductance of VDAC (especially of the VDAC1 isoform) by different drugs (left part) triggers apoptosis. In addition, disruption of the interaction of VDAC with the soluble, cytosolic glycolytic enzyme hexokinase II (HKII) or with membrane-inserted anti-apoptotic proteins Bcl-2 or Bcl-xL by specific targeting peptides (right part) equally leads to cell death. See text (par. 2.3 and 4.1) for further details.

Fig. 3

Role of the voltage-dependent potassium channel Kv1.3 and its pharmacological modulation in cell death. A) The mitochondrial counterpart of the plasmamembrane-located Kv1.3 channel (mtKv1.3) can be blocked by membrane-inserted Bax, through the specific K128 residue. The block of channel activity causes an initial hyperpolarization followed by ROS release and MPTP opening. B) Membrane-impermeant toxin inhibitors of Kv1.3 capable of reaching only the plasma-membrane-located Kv1.3 are unable to trigger cell death, indicating that mtKv1.3 is the channel whose function is relevant for apoptosis. C) Membrane-permeant, mitochondriotropic inhibitors PAPTP and PCARBTP (indicated as PCARB) efficiently trigger the same series of events shown in A), leading to cell death of cancer cells in vitro and in orthotopic tumor models. D) The more soluble derivative of the small molecule inhibitor of Kv1.3 (and of mtKv1.3) PAP-1, named PAP-1-MHEG promotes ROS production by acting on mtKv1.3 that is strictly interacting with the respiratory chain complex I, thereby amplifying the ROS-producing effect of the drug that may transfer electrons from complex I to oxygen. The See text (par. 2.4 and 3.2) for details.