Chou Chuan-Chu, Lunn Charles A, Murgolo Nicholas J
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Expert Rev Mol Diagn. 2008 Mar;8(2):179-87. doi: 10.1586/14737159.8.2.179.
KCa3.1 is a calcium-activated intermediate-conductance potassium ion channel. In humans the channel is expressed in several secretory organs and subtypes of hematopoietic cells, but not detected in excitable tissues. The mRNA level for KCa3.1 is upregulated in activated leukocytes, mitogen-induced endothelial cells and vascular smooth muscle cells, and several types of human cancers, suggesting a possible role for the channel in inflammatory and oncology diseases. Several potent and selective KCa3.1 blockers, including clotrimazole and its analogs TRAM-34 and ICA-17043, have been used to investigate the involvement of the channel in human disease. The compounds have been shown to suppress the proliferation of several cancer cells in vitro and the growth of the corresponding cancers in vivo, consistent with an oncologic indication. TRAM-34 also ameliorates symptoms in experimental autoimmune encephalomyelitis and several models of cardiovascular diseases, arguing for a role of the channel in inflammatory diseases. These results suggest several important opportunities for therapeutics based on KCa3.1. Further efforts will establish the optimal indication for these ion channel inhibitors.
KCa3.1是一种钙激活的中等电导钾离子通道。在人类中，该通道在多个分泌器官和造血细胞亚型中表达，但在可兴奋组织中未检测到。KCa3.1的mRNA水平在活化的白细胞、丝裂原诱导的内皮细胞和血管平滑肌细胞以及几种人类癌症中上调，这表明该通道在炎症和肿瘤疾病中可能发挥作用。几种强效且选择性的KCa3.1阻滞剂，包括克霉唑及其类似物TRAM-34和ICA-17043，已被用于研究该通道在人类疾病中的作用。这些化合物已被证明在体外可抑制多种癌细胞的增殖，并在体内抑制相应癌症的生长，这与肿瘤学适应症一致。TRAM-34还可改善实验性自身免疫性脑脊髓炎和几种心血管疾病模型中的症状，这表明该通道在炎症性疾病中发挥作用。这些结果提示了基于KCa3.1的治疗方法的几个重要机会。进一步的研究将确定这些离子通道抑制剂的最佳适应症。
