KCa3.1: target and marker for cancer, autoimmune disorder and vascular inflammation?
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.
Chou
Chuan-Chu
CC
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. chuan-chu.chou@spcorp.com
Lunn
Charles A
CA
Murgolo
Nicholas J
NJ
D000818:Animals; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects; D014657:Vasculitis / Q000188:drug therapy / Q000378:metabolism*
D014408:Biomarkers, Tumor; D002121:Calcium Channel Blockers; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D008934:Mitogens; D009363:Neoplasm Proteins; D012333:RNA, Messenger