Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges

Abstract

Ion channels are key regulators of cancer cell pathophysiology. They contribute to a variety of processes such as maintenance of cellular osmolarity and membrane potential, motility (via interactions with the cytoskeleton), invasion, signal transduction, transcriptional activity and cell cycle progression, leading to tumour progression and metastasis. Ion channels thus represent promising targets for cancer therapy. Ion channels are attractive targets because many of them are expressed at the plasma membrane and a broad range of existing inhibitors are already in clinical use for other indications. However, many of the ion channels identified in cancer cells are also active in healthy normal cells, so there is a risk that certain blockers may have off-target effects on normal physiological function. This review describes recent research advances into ion channel inhibitors as anticancer therapeutics. A growing body of evidence suggests that a range of existing and novel Na + , K + , Ca 2+ and Clchannel inhibitors may be effective for suppressing cancer cell proliferation, migration and invasion, as well as enhancing apoptosis, leading to suppression of tumour growth and metastasis, either alone or in combination with standard of care therapies. The majority of evidence to date is based on preclinical in vitro and in vivo studies, although there are several examples of ion channel targeting strategies now reaching early phase clinical trials. Given the strong links between ion channel function and regulation of tumour growth, metastasis and chemotherapy resistance, it is likely that further work in this area will facilitate the development of new therapeutic approaches which will reach the clinic in the future.

Modifications of Plasma Membrane Organization in Cancer Cells for Targeted Therapy

“…This chapter focuses on the main anticancer strategies based on IC and discusses examples of their application. As a complementary review of ion channel inhibitors, we refer to [91].…”

Voltage-Gated Potassium Channels as Regulators of Cell Death

“…Kv channels influence cell cycle progression not only by setting the membrane potential, but also, as a consequence, by contributing to ensuring the driving force for calcium entry (for reviews see e.g., Cahalan and Chandy, 2009;Urrego et al, 2014) and the exit of chloride ions (and the resulting cell shrinkage). Accordingly, Kv channel expression changes during the progression through the different phases of the cell cycle, as first revealed more than 30 years ago in T lymphocyte development (McKinnon and Ceredig, 1986).…”

“…In this review we will focus our attention on the members of the classical voltage-gated Kv channel family, who were among the first channels to be linked to the regulation of cell cycle ( DeCoursey et al, 1984 ; McKinnon and Ceredig, 1986 ; Arcangeli et al, 1993 ; Pardo et al, 1998 ) and cell death ( Szabo et al, 1996 ; Gómez-Angelats et al, 2000 ), both processes instrumental to cancer progression (for recent reviews see e.g., Pardo and Stuhmer, 2014 ; Serrano-Novillo et al, 2019 ; Capatina et al, 2020 ). Indeed, dysregulated cell cycle leading to unlimited proliferation as well as apoptosis resistance are two hallmarks of cancer cells ( Hanahan and Weinberg, 2000 ).…”

Inhibition of the Na+/K+-ATPase by cardiac glycosides suppresses expression of the IDO1 immune checkpoint in cancer cells by reducing STAT1 activation

“…Changes in ion transport drive a number of cellular phenotypes associated with cancer (5). Signal transduction, cytoskeletal remodelling, and cell motility underpinning cell migration (6,7), growth and cell cycle progression (8)(9)(10), and gene expression (11,12) can all be impacted by altered ion flux.…”