66 Current Medicinal Chemistry, 2009, 16, 66-93 Targeting Ion Channels in Cancer: A Novel Frontier in Antineoplastic Therapy A. Arcangeli*,1, O. Crociani1, E. Lastraioli1, A. Masi1, S. Pillozzi1 and A. Becchetti2 1Department of Experimental Pathology and Oncology, University of Firenze, Italy; 2Department of Biotechnology and Biosciences, University of Milano-Bicocca, Italy 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 spe- cific 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 in- creasingly 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 Ca2+ fluxes and thus the cell cycle machinery. Their effects on mitosis can also de- pend on regulation of cell volume, usually in cooperation with chloride channels. However, ion channels are also impli- cated in late neoplastic stages, by stimulating angiogenesis, mediating the cell-matrix interaction and regulating cell motil- ity. 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 re- ceptors. 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 pro- duce 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. Keywords: Leukemia, glioma, breast cancer, colorectal cancer, prostate cancer, ion channels, Kv 1.3, KCa 3.1, hEAG-1, Kv 10.1, hERG1, Kv 11.1, Nav 1.5, Nav 1.7. 1. CURRENT VIEWS ON CANCER BIOLOGY AND The molecular dissection of neoplastic progression po- THERAPY tentially opens the way to the development of drugs address- ing tumor-specific processes. The many recent efforts de- The molecular biological revolution that has reshaped voted to this task have led to substantial improvement in biomedical research over the past three decades has also treatment. For instance, novel selective inhibitors of receptor changed dramatically our understanding of the origins of and non receptor tyrosine kinases, pivotal regulators of cell neoplasia. The main new notion is probably that cancer cells survival and proliferation, are now available for clinical use. are mutants. They often carry somatic mutations of tumor- An excellent example is the human Epidermal Growth Fac- related genes, although other modifications such as gene tor (EGF) receptor-2 (HER2). Herceptin, the therapeutic amplification or inactivation can also occur, possibly caused monoclonal antibody against HER2 approved by the Food by epigenetic mechanisms. The systematic search for genes and Drug Administration, has been used to treat over particularly liable to mutate during tumour progression has 150,000 women with breast cancer. Considerable advances led to the concept that cancer is a multistep process. Early have also been made in anti-angiogenesis therapy, because steps comprise alteration of a relatively small number of inhibitors of the Vascular Endothelial Growth Factors genes implicated in cell proliferation, apoptosis and differen- (VEGFs) and their receptors revert the tumor-associated tiation. As a consequence, cell clones are produced which are blood vessels to a quasi-normal state. Besides hampering cell invulnerable from apoptosis and capable of unlimited prolif- proliferation, this treatment allows chemotherapeutic drugs eration. The growing tumor mass then stimulates angiogene- to access the tumor’s core. By combining new specific sis, in order to sustain itself. At later stages, phenotypic fea- agents with traditional chemotherapy, patient survival is tures are selected that enable cells to invade and colonize often significantly prolonged. Although many questions still (metastasize) neighbouring or even distant tissue, and even- linger as to the choice of the best drug combination and tually to evade and overcome immune response [1]. regimen calibration, there is little doubt that targeted thera- pies are changing care and prognosis for the better [1]. Here, we review the growing experimental and preclini- *Address correspondence to this author at the Department of Experimental cal evidence indicating that ion channels should be included Pathology and Oncology, University of Firenze, Italy; Tel: +39 055 among the novel targets for cancer therapy, which may open 4598206; Fax: +39 055 4598900; E-mail: [email protected] 0929-8673/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Targeting Ion Channels in Cancer Current Medicinal Chemistry, 2009 Vol. 16, No. 1 67 an entire pharmaceutical and clinical field. Why ion chan- the few pharmaceutically tractable molecular classes. A nels? First, their expression is often grossly altered in human major advantage is their accessibility from the extracellular cancers. Second, channel dysfunction can have a strong side, which makes ion channel modulators particularly effec- impact on cell physiology and signaling, with ensuing effects tive. on cancer progression. Third, ion channels represent one of Fig. (1). Dendrogram of the different families of K+ Channels, Voltage-Gated Ca2+ Channels (VGCC) and Voltage-Gated Na+ Chan- + + + nels (VGSC). For K Channels, the four main families are shown: Voltage-Gated K Channels (VGKC or Kv ), Inwardly-Rectifying K 2+ + + Channels (KIR), Ca -activated K Channels (KCa ) and Two-pore K Channels (K2p). Subtypes are named according to the IUPHAR nomen- clature. The channel types mainly expressed in cancer cells are highlighted. Box: comparison of IUPHAR, HGNC and common names for the K+ channels discussed in the text and tables. 68 Current Medicinal Chemistry, 2009 Vol. 16, No. 1 Arcangeli et al. 2. ION CHANNEL STRUCTURE AND PHYSIOLOGY: Finally, the Transient Receptor Potential (TRP) gene su- A BRIEF SURVEY perfamily is also related to the VGC’s, thus retaining the structural features outlined above. Subunits form homo- or Ion channels are integral membrane proteins that control heterotetrameric channels. Six TRP families are known passive ion fluxes, by switching between non conductive (TRPC, TRPV, TRPM, TRPA, TRPP and TRPML), with (‘closed’) and conductive (‘open’) conformational states. different permeability ratios between Ca2+ and monovalent Such a ‘gating’ process (activation) is often driven by trans- cations, ranging from nil to very high. These proteins are membrane voltage (Vm) or specific ligands, although other widely distributed in mammalian tissues and have been im- mechanisms are possible. Many types of ion channels exist, plicated in several human diseases, including cancer. The with widely different degrees of ion selectivity and kinetic physiological meaning of altered TRP channel expression in features, which produces great functional flexibility. Volt- tumors is under intense study [8]. age-gated channels (VGCs) usually regulate cellular excit- Fig. (1) shows a dendrogram of VGCs with the corre- ability and shape the action potential. In addition, by control- 2+ sponding IUPHAR nomenclature. Channels that have been ling transmembrane Ca fluxes, they can trigger exocytosis detected in cancer cells are highlighted. For the K+ channels and muscle contraction. Ligand-gated channels typically discussed in the text, both the IUPHAR and the common exert synaptic roles. The integrated action of different chan- nel types controls cell volume, transepithelial ion flow, sen- names are given (box). sory transduction, synaptic function and many other physio- The other side of the ion transport coin is constituted by logical processes. ion pumps and other transporters. Knowledge about the transporters’ role in neoplasia is however less extensive than If the stimulus is interrupted, channels close (deactiva- it is for ion channels. Therefore, we will limit our discussion tion). Otherwise, they often enter a further non conductive + + + state, by a process named inactivation for voltage-gated to some specific issues concerning H fluxes and the Na /K pump, omitting