Ion Channels as Promising Therapeutic Targets for Melanoma

Abstract

Even cancer is far from being considered a channelopathy; the field of ion and protein channel research in cancer is highly important as an emerging and proven point of intervention in disease. Like membrane receptors, ion channels are directly connected with and sensitive to the extracellular environment. During the last decade, the number of ionchannel types expressed in various cancers, including melanoma, was rapidly increased. Moreover several ion channels are selectively expressed in aggressive cancers and seem to be implicated in metastasis development. The growing number of patents relative to cancer therapy targeting channel proteins testifies to the interest of such novel therapeutic approaches. The physiological significance of ion channels and transporters, as illustrated by the award of four Nobel Prizes in Physiology or Medicine (1963; 1991) and Chemistry (1997, 2003), is now accepted and established. Unlike transporters and exchangers, channel proteins form a pore through membranes allowing the selective passage of one or more ions (e.g. K+, Na+, Cl-), molecules (water) or charged atoms, through the lipid bilayer that is impermeable to these compounds. The modalities of channel opening or activation are diverse and varied: this can be performed by an external molecular stimulus (e.g. ligand), by a mechanical stimulus (e.g. cell volume, membrane tension or stretch), by electric stimuli (e.g. changes in membrane potential), by an intracellular second messenger (e.g. calcium, cAMP). Thus the classification of the channels (IUPHAR classification) is based on the channel activation mode and on the selective permeability of molecular species specific to each channel. Channel proteins are involved in the control of numerous and various physiological functions. Basically, these channels are responsible for a universal property for cellular membranes: the existence of resting membrane potential. Ion channels, mainly studied in excitable cells like muscle and neurons, are responsible for the transmission of the electric signals triggering physiological and biological phenomena such as nerve conduction or the cellular phenomenon of excitation contraction coupling. Ion transporter (Na+/K+-ATPase or simply known as sodium pump) is the membrane pump that generates the Na+ and K+ gradients across the plasma membrane, driving many physiological processes. Another