K ⁺ Channels as Therapeutic Targets in Oncology

Abstract

Ion channels are involved in a variety of tumors. In particular, potassium channels are expressed abnormally in many cancer types, where their pharmacologic manipulation impairs tumor progression. Since this group of molecules has been successfully targeted for decades in other therapeutic areas, there is a significant body of knowledge on the pharmacology of potassium channels. Several groups of potassium channels with defined molecular identities have been proposed as candidates for therapeutic intervention. The strategies put forward range from classical small molecule blockade to gene therapy approaches, and include the use of potassium channels as targets for adjuvant therapy. We will discuss the reasons for these proposals and explore possible future developments.

The Inhibition of KCa3.1 Channels Activity Reduces Cell Motility in Glioblastoma Derived Cancer Stem Cells

“…In the normal adult murine brain the KCa3.1 current has only been reported on activated microglia [42], brain capillary endothelial cells [43], Purkinje cells [44], and in a subpopulation of astrocytes involved in neurovascular coupling [45]–[47] [8]. Taken together, these data would suggest that in murine brain the functional expression of the KCa3.1 channel is confined to specific astrocytic cell subpopulations.…”

“…Several properties of cancer, including glioblastoma, are influenced by misregulation of ion channel expression or function [6]–[8]. Reduced expression of inward rectifier K channels [9] and increased expression of amiloride-sensitive Na channels [10], voltage-activated Cl channels [11], and BK channels [12] have been reported in several gliomas, compared to normal astrocytes.…”

Membrane potential and cancer progression

“…For example, bioelectrical impedance analysis, which determines tissue electrical properties, has shown promise as a prognostic indicator to monitor cancer progression (Gupta et al, 2004a,b); , and recently, the development of non-invasive, voltage-sensitive optical probes provides a potential approach for in vivo V m measurement (Adams and Levin, 2012; Chernet and Levin, 2013). Considering the vast array of therapeutic drugs that target ion channels (Sontheimer, 2008; Stuhmer and Pardo, 2010; D'amico et al, 2013; Djamgoz and Onkal, 2013), modulating the V m of malign tissues by adjusting the activities of varies ion channels/transporters may provide a convenient clinical approach.…”

An inhibitor of K+ channels modulates human endometrial tumor-initiating cells

“…Potassium (K + ) ion channels are important contributors to the malignant phenotype in cancer cells and as such have been shown to drive progression of cancers of the breast, prostate, endometrium and brain [1-8]. Multiple mechanisms exist by which K + channels exert their oncogenic functions.…”

“…For example, K + channels have been shown to modulate cell cycle progression to increase cell proliferation as well as promote cytoskeletal remodeling to enhance invasion and migration [9-21]. Inhibitors of K + channels thus constitute putative anti-cancer drugs [1,2,22-26], though to date none of these antagonists have been explored in a clinical trial setting for any type of cancer.…”