Potassium channels: New targets in cancer therapy

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Abstract

Background: Potassium channels (KCh) are the most diverse and ubiquitous class of ion channels. KCh control membrane potential and contribute to nerve and cardiac action potentials and neurotransmitter release. KCh are also involved in insulin release, differentiation, activation, proliferation, apoptosis, and several other physiological functions. The aim of this review is to provide an updated overview of the KCh role during the cell growth. Their potential use as pharmacological targets in cancer therapies is also discussed. Methods: We searched PubMed (up to 2005) and identified relevant articles. Reprints were mainly obtained by on line subscription. Additional sources were identified through cross-referencing and obtained from Library services. Results: KCh are responsible for some neurological and cardiovascular diseases and for a new medical discipline, channelopathies. Their role in congenital deafness, multiple sclerosis, episodic ataxia, LQT syndrome and diabetes has been proven. Furthermore, a large body of information suggests that KCh play a role in the cell cycle progression, and it is now accepted that cells require KCh to proliferate. Thus, KCh expression has been studied in a number of tumours and cancer cells. Conclusions: Cancer is far from being considered a channelopathy. However, it seems appropriate to take into account the involvement of KCh in cancer progression and pathology when developing new strategies for cancer therapy.

Introduction

Cancer is a multifactor process that involves several temporal steps. Cells first acquire a phenotype through the altered expression of proteins and genes. Afterwards, tumour cells proliferate massively and do not undergo apoptosis. Chemotherapy and radiosensitization have been widely used to block this progression. However, the use of these therapies is not synonymous with success. Nucleoside analogues have been widely used as a first attempt to control the cell cycle. These molecules are taken up by the cells by means of membrane transport systems. Nucleoside derivatives (i.e. fludarabine or gemcitabine, among others) used in cancer and antiviral therapies interfere with nucleoside metabolism and DNA replication, thus inducing their pharmacological effects [1]. In fact, nucleoside uptake is induced during proliferation. The inhibition of nucleoside transport systems by nucleoside derivatives arrests the cell cycle in the S phase [2], [3], [4], [5]. Several nucleoside carriers have been described and molecularly characterized. Their activities overlap and their expression depends on the tissue and the differentiation status of the cell [5], [6].

Although a lot of effort is involved in designing individual treatments, most current strategies are not selective. They may be harmful and are sometimes unsuccessful. In some cases, this lack of efficiency could be explained by tumour cells’ extraordinary ability to develop a multidrug resistance (MDR) phenotype in response to chemotherapy [7], [8]. Thus, adaptive regulation, overlapped transport activities and their expression are the main obstacles in cancer therapeutics.

Novel technologies such as genomics and proteomics have increased the number of human genes known to be differentially expressed in normal and malignant tissues. We have entered a new era, leaving cytotoxic approaches behind to focus on mechanisms based on gene therapy and pharmacogenomics. This new perspective has produced a large body of evidence indicating that KCh could play a relevant role in cancer therapy.

Targeting potassium channels for cancer therapy could give rise to successful strategies for the following reasons:

  • i)

    KCh are involved in cell proliferation as they control cell cycle progression.

  • ii)

    KCh show cell and tissue-specific expression.

  • iii)

    These proteins are highly sensitive to synthetic blockers and natural peptides, leading pharmaceutical companies to design more effective and selective molecules.

  • iv)

    Current therapies for nerve and cardiac diseases successfully target KCh and have few side effects.

  • v)

    Impaired expression of KCh has been detected in a number of cancer and tumour cells.

In addition, overexpression of KCh has been described in some MDR cell lines and K+ channels effectors may partially reverse the MDR phenotype [7]. Furthermore, KCh control upstream nucleoside derivative uptake pathways [9]. Therefore, a combination of therapies involving chemotherapeutic agents and K+ channels blockers has been proposed.

Section snippets

Methods

The criteria for the data selection in this review were the evidences obtained through an electronic data base search in PubMed of literature mainly published in the last 8 years (1998–2005). In addition, approximately one-fourth of the references were from the last two years. Only relevant papers prior to these dates were also considered. The searches were limited to articles published in English. Various combinations were searched using the keywords “potassium channels”, “cancer”, “cell

Criteria for the selection of studies

Because the aim of this review is to highlight the involvement of potassium channels in cancer progression and pathology, studies were selected for citing based on their relevance to this purpose. The evidences may also suggest that these proteins can be used as tumour markers in cancer detection. In addition, the latest literature indicates that the time has come to consider potassium channels when developing new strategies for cancer therapy. The information has been summarized descriptively

Conclusions

Potassium channels in cell membranes regulate cellular excitability and proliferation. The central role of these ion channels in cell function has made them the target of several channelopathies. In light of the increasing amount of evidence showing that KCh are involved in cell proliferation and tumour growth, it seems that these proteins could be considered a pharmacological tool during cancer progression and pathology. The persistence of the MDR phenotype handicaps the treatment and the

Acknowledgements

The work carried out by the Molecular Physiology Laboratory was funded by grants from the Universitat de Barcelona, the Generalitat de Catalunya and the Ministerio de Educación y Ciencia (MEC), Spain awarded to AF. RV is the recipient of a fellowship from the Universitat de Barcelona. NV and RM hold fellowships from the MEC. MR-F is a research fellow of the Generalitat de Catalunya. The editorial assistance of the Language Advisory Service from the University of Barcelona is also acknowledged.

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