Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges
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,
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Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges Alina L. Capatina, Dimitris Lagos, and William J. Brackenbury
Contents 1 Introduction 2 Na+ Channel Inhibitors 3 K+ Channel Inhibitors 4 Ca2+ Channel Inhibitors 5 Cl Channel Inhibitors 6 Combinatorial Treatments 7 Conclusions and Future Perspectives References
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 A. L. Capatina Department of Biology, University of York, York, UK D. Lagos Hull York Medical School, York, UK York Biomedical Research Institute, University of York, York, UK W. J. Brackenbury (*) Department of Biology, University of York, York, UK York Biomedical Research Institute, University of York, York, UK e-mail: [email protected]
A. L. Capatina et al.
Na+, K+, Ca2+ and Cl channel 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 channeltargeting 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. Keywords Calcium · Cancer · Chloride · Inhibitors · Ion channels · Immunotherapy · Potassium · Sodium
1 Introduction Traditional chemotherapeutic approaches have been successfully used as cancer treatments for decades, partially due to their generalised, anti-proliferative and cytotoxic activity (DeVita and Chu 2008). However, the lack of specificity of chemotherapy is a limiting factor in the treatment of more advanced tumours and acquired resistance. This has driven the development of targeted therapies, such as monoclonal antibodies, small molecule pathway inhibitors and immune checkpoint i
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