Targeting Ion Channels in Leukemias: A New Challenge for Treatment

Abstract

Leukemias, as other cancers, bear several genetic alterations of tumor-related genes, such as point mutations, translocations, epigenetic modifications, often accompanied by gene amplification or inactivation. The identification of tumor-related genes provides considerable insight into the biology of leukemias and opens the way to more specific pharmacological treatments. These genes comprise several ion channels and pumps, as the transport mechanisms associated with volume control, proliferation and apoptosis are often altered in cancers. In leukemic cells, such changes are observed as early as the stem cell stage. Ion channels can regulate other malignant features, such as lack of differentiation, increased migratory and invasive phenotype and chemoresistance. The role of certain voltage-gated K(+) channels, such as K(v)11.1 (also known as hERG1) can be largely attributed to modulation of cell adhesion to the extracellular matrix (ECM). K(v)11.1 exerts pleiotropic regulatory effects by forming multiprotein membrane complexes with integrin receptors in both acute myeloid leukemias (AML) and acute lymphoblastic leukemias (ALL). By recruiting growth factor and chemokine receptors, these complexes form signaling hubs that control neoplastic progression. Work in mice shows that blocking K(v)11.1 has a protective effect in acute leukemias. Ion channels are most promising targets for anti-leukemic therapy, because of their accessibility from the extracellular side and the thorough understanding of their pharmacology. In ALL cells, K(v)11.1 inhibitors abrogate the protective effect of bone marrow stromal cells and enhance the cytotoxicity of some common antileukemic drugs. Hence, ion channel modulators could overcome chemoresistance in acute leukemias, a major hindrance to therapeutic success.

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications

“…We can conclude that, in gastric cancer, hERG1 behaves as a cell-cycle device, capable of regulating cell proliferation (12,13), as well as a progression-related gene, mainly involved in the regulation of tumor angiogenesis. Although the impact of hERG1 on cell cycle could be traced back to the regulation of intracellular Ca 2þ levels as a consequence of a hERG1-dependent regulation of the membrane potential value (28), the effects on tumor progression could be related to the hERG1-dependent effect on cell signaling, well documented in several types of cancer (3,4,29). This latter ability makes hERG1 not only a canonical ion channel, but also a membrane protein able to influence the expression of tumor-related genes in an unconventional manner.…”

New Pyrimido-Indole Compound CD-160130 Preferentially Inhibits the KV11.1B Isoform and Produces Antileukemic Effects without Cardiotoxicity

“…Such screening is mandatory for approval for clinical use. Ample evidence shows that K V 11.1 channels are often aberrantly expressed in solid human cancers (Arcangeli, 2005) as well as in leukemias (Pillozzi et al, 2002(Pillozzi et al, , 2007Arcangeli et al, 2012). K V 11.1 controls different aspects of cell malignancy, from proliferation and survival, to transendothelial migration and bloodstream invasion (Arcangeli et al, 2012).…”

“…Ample evidence shows that K V 11.1 channels are often aberrantly expressed in solid human cancers (Arcangeli, 2005) as well as in leukemias (Pillozzi et al, 2002(Pillozzi et al, , 2007Arcangeli et al, 2012). K V 11.1 controls different aspects of cell malignancy, from proliferation and survival, to transendothelial migration and bloodstream invasion (Arcangeli et al, 2012). Furthermore, in acute lymphoid leukemia (ALL), the K V 11.1 function is necessary for the development of tumor resistance to chemotherapy (Pillozzi et al, 2011), as blocking K V 11.1 decreases tumor growth in mice xenografted with leukemic cells, and in particular with chemoresistant cells (Pillozzi et al, 2011).…”

“…On the contrary, leukemias mainly express K V 11.1B (Crociani et al, 2003;Pillozzi et al, 2007), and overexpression of the KCNH2b transcript in pediatric T-ALL identifies a patients' subgroup with a worse prognosis (Pillozzi et al, 2014). Therefore, one possibility of circumventing the risk of developing torsade de pointes in patients treated with K V 11.1 blockers would be to selectively inhibit K V 11.1B, the leukemia-specific channel isoform (Arcangeli et al, 2012).…”

Upregulation of the large conductance voltage- and Ca2+-activated K+ channels by Janus kinase 2

“…JAK2 inhibitors are thus considered for the treatment of myeloproliferative disorders (4,19,39,41,44,59). The machinery involved in the regulation of cell proliferation includes K ϩ -channel activity (2,29,40,61,62). The K ϩ channels are further implicated in tumor cell migration (52).…”