Department of Experimental Pathology and Oncology, University of Florence, Viale G.B. Morgagni, 50, 50134 Firenze, Italy.
Curr Med Chem. 2012;19(5):683-96. doi: 10.2174/092986712798992093.
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.
白血病与其他癌症一样，存在多种肿瘤相关基因的遗传改变，如点突变、易位、表观遗传修饰，常伴有基因扩增或失活。肿瘤相关基因的鉴定为白血病的生物学提供了重要的认识，并为更具特异性的药物治疗开辟了道路。这些基因包括几个离子通道和泵，因为与体积控制、增殖和凋亡相关的运输机制在癌症中经常发生改变。在白血病细胞中，这种变化早在干细胞阶段就可以观察到。离子通道可以调节其他恶性特征，如缺乏分化、增加迁移和侵袭表型以及化疗耐药性。某些电压门控 K(+)通道（如 K(v)11.1（也称为 hERG1））的作用在很大程度上归因于调节细胞与细胞外基质（ECM）的黏附。K(v)11.1 通过与急性髓系白血病（AML）和急性淋巴细胞白血病（ALL）中的整合素受体形成多蛋白膜复合物，发挥多效性调节作用。通过招募生长因子和趋化因子受体，这些复合物形成信号枢纽，控制肿瘤的进展。小鼠研究表明，阻断 K(v)11.1 在急性白血病中具有保护作用。离子通道是抗白血病治疗最有前途的靶点，因为它们可以从细胞外侧面进入，并且对其药理学有深入的了解。在 ALL 细胞中，K(v)11.1 抑制剂可消除骨髓基质细胞的保护作用，并增强某些常见抗白血病药物的细胞毒性。因此，离子通道调节剂可以克服急性白血病的化疗耐药性，这是治疗成功的主要障碍。
