Targeting Ion Channels in Cancer: A Novel Frontier in Antineoplastic Therapy

Abstract

Targeted therapy is considerably changing the treatment and prognosis of cancer. Progressive understanding of the molecular mechanisms that regulate the establishment and progression of different tumors is leading to ever more specific and efficacious pharmacological approaches. In this picture, ion channels represent an unexpected, but very promising, player. The expression and activity of different channel types mark and regulate specific stages of cancer progression. Their contribution to the neoplastic phenotype ranges from control of cell proliferation and apoptosis, to regulation of invasiveness and metastatic spread. As is being increasingly recognized, some of these roles can be attributed to signaling mechanisms independent of ion flow. Evidence is particularly extensive for K(+) channels. Their expression is altered in many primary human cancers, especially in early stages, and they frequently exert pleiotropic effects on the neoplastic cell physiology. For instance, by regulating membrane potential they can control Ca(2+) fluxes and thus the cell cycle machinery. Their effects on mitosis can also depend on regulation of cell volume, usually in cooperation with chloride channels. However, ion channels are also implicated in late neoplastic stages, by stimulating angiogenesis, mediating the cell-matrix interaction and regulating cell motility. Not surprisingly, the mechanisms of these effects are manifold. For example, intracellular signaling cascades can be triggered when ion channels form protein complexes with other membrane proteins such as integrins or growth factor receptors. Altered channel expression can be exploited for diagnostic purposes or for addressing traceable or cytotoxic compounds to specific neoplastic tissue. What is more, recent evidence indicates that blocking channel activity impairs the growth of some tumors, both in vitro and in vivo. This opens a new field for medicinal chemistry studies, which can avail of the many available tools, such as blocking antibodies, antisense oligonucleotides, small interfering RNAs, peptide toxins and a large variety of small organic compounds. The major drawback of this approach is that some ion channel blockers produce serious side effects, such as cardiac arrhythmias. Therefore, drug developing efforts aimed at producing less harmful compounds are needed and we discuss possible approaches toward this goal. Finally, we propose that a novel therapeutic tactic could be developed by unlocking ion channels from multiprotein membrane signaling complexes.

Targeting proliferation of chronic lymphocytic leukemia (CLL) cells through KCa3.1 blockade

“…1,2 Given the importance of controlling Ca 2 þ -influx, there is growing interest in selective K þ channel blockers to suppress cell proliferation in autoimmune diseases and cancer. [3][4][5] Chronic lymphocytic leukemia (CLL) is a heterogeneous lymphoproliferative malignancy of clonally expanded CD5 þ CD19 þ B cells. 6 CLL cells are presumably derived from an activated antigen-experienced precursor (IgD þ CD27 þ ).…”

“…4,5 MDS/MPN-U is a rare diagnosis, making up o5% of all myeloid disorders. 6 Accordingly, clinical characteristics and the natural history of patients with MDS/MPN-U are not well established, although poor prognosis among patients with MDS/MPN-U (without RARS-T) has been suggested in small series to date.…”

“…6 Accordingly, clinical characteristics and the natural history of patients with MDS/MPN-U are not well established, although poor prognosis among patients with MDS/MPN-U (without RARS-T) has been suggested in small series to date. 5,6 No standard prognostic or treatment algorithms for MDS/MPN-U exist. Our aim was to evaluate patients with a confirmed diagnosis of MDS/MPN-U without RARS-T, to provide insights into the nature of this unique myeloid overlap syndrome with implications to appropriate treatment strategies.…”

Melatonin affects voltage-dependent calcium and potassium currents in MCF-7 cell line cultured either in growth or differentiation medium

“…The diverse types of human cancers may show a peculiar biophysical profile with an atypical ion channels activity (Abdul et al, 2003;Arcangeli et al, 2009). In such perspective, it might be worth to better characterize this issue with the aim of designing efficient ionic channel inhibitors/modulators that may potentially affect cancer therapy.…”

“…The rationale for this research originates from the evidence that several ionic channels have a key role in proliferation and differentiation and can be therefore considered as new targets for cancer therapy (Arcangeli et al, 2009). …”