By controlling ion fluxes at multiple time scales, ion channels shape rapid cell signals, such as action potential and synaptic transmission, as well as much slower processes, such as mitosis and cell migration. As is currently increasingly recognized, a variety of channel types are involved in cancer hallmarks, and regulate specific stages of neoplastic progression. Long-term in vitro work has established that inhibition of these ion channels impairs the growth of cancer cells. Recently, these studies have been followed up in vivo, hence revealing that ion channels constitute promising pharmacological targets in oncology. The channel proteins can be often accessed from the extracellular milieu, which allows use of lower drug doses and decrease untoward toxicity. However, because of the central physiological roles exerted by ion channels in excitable cells, other types of side effects may arise, the gravest of which is cardiac arrhythmia. A paradigmatic case is offered by Kv11.1 (hERG1) channels. HERG1 blockers attenuate the progression of both hematologic malignancies and solid tumors, but may also lead to the lengthening of the electrocardiographic QT interval, thus predisposing the patient to ventricular arrhythmias. These side effects can be avoided by specifically inhibiting the channel isoforms which are highly expressed in certain tumors, such as Kv11.1B and the neonatal forms of voltage-gated Na(+) channels. Preclinical studies are also being explored in breast and prostate cancer (targeting voltage-gated Na(+) channels), and gliomas (targeting CLC-3). Overall, the possible approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1) the development of specific inhibitors for the channel subtypes expressed in specific tumors; (2) drug delivery into the tumor by using antibodies or nanotechnology-based approaches; (3) combination regimen therapy and (4) blocking specific conformational states of the ion channel. We believe that expanding this relatively neglected field of oncology research might lead to unforeseen therapeutic benefits for cancer patients.

中文翻译：

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癌症治疗的新观点：靶向离子通道。

通过在多个时间尺度上控制离子通量，离子通道可以塑造快速的细胞信号，例如动作电位和突触传递，以及速度更慢的过程，例如有丝分裂和细胞迁移。如目前日益认识到的，癌症的特征涉及多种通道类型，并调节肿瘤进展的特定阶段。长期的体外研究表明，抑制这些离子通道会损害癌细胞的生长。最近，在体内对这些研究进行了跟踪，因此揭示了离子通道构成了肿瘤学中有希望的药理学靶标。通道蛋白通常可以从细胞外环境中获得，从而可以使用较低的药物剂量并降低不良的毒性。然而，由于离子通道在可兴奋细胞中发挥重要的生理作用，因此可能会出现其他类型的副作用，其中最严重的是心律失常。Kv11.1（hERG1）通道提供了一个典型案例。HERG1阻滞剂可减弱血液系统恶性肿瘤和实体瘤的进展，但也可能导致心电图QT间隔延长，从而使患者易患室性心律不齐。这些副作用可以通过特异性抑制某些肿瘤（例如Kv11.1B和电压门控Na（+）通道的新生儿形式）中高度表达的通道亚型来避免。临床前研究也正在乳腺癌和前列腺癌（靶向电压门控的Na（+）通道）和神经胶质瘤（靶向CLC-3）中进行探索。全面的，在肿瘤学中提高离子通道靶向疗效和安全性的可能方法包括：（1）开发针对特定肿瘤中表达的通道亚型的特异性抑制剂；（2）使用抗体或基于纳米技术的方法将药物输送到肿瘤中；（3）联合方案治疗和（4）阻断离子通道的特定构象状态。我们认为，扩大这一相对被忽视的肿瘤学研究领域可能会为癌症患者带来无法预料的治疗益处。（3）联合方案治疗和（4）阻断离子通道的特定构象状态。我们认为，扩大这一相对被忽视的肿瘤学研究领域可能会为癌症患者带来无法预料的治疗益处。（3）联合方案治疗和（4）阻断离子通道的特定构象状态。我们认为，扩大这一相对被忽视的肿瘤学研究领域可能会为癌症患者带来无法预料的治疗益处。