Cell migration causing metastasis and tissue invasion is a major challenge in cancer therapy. Aquaporin-1 (AQP1) channel expression is upregulated in several aggressive cancers; in contrast AQP1 deletion impedes migration and reduces metastasis. In diverse motile cells from amoebae to human, AQP1-related channels are localized in lamellipodial leading edges where they are necessary for fast migration, but the mechanism remained a mystery. Our research group has shown that AQP1 is more than just a water channel. AQP1 also acts as a non-selective cation channel gated by cGMP. Water and ions traverse pharmacologically distinct pathways in AQP1, and both are essential for rapid migration. The pro-migratory effect of AQP1 is blocked by novel derivatives of bumetanide we designed and characterized. The most potent of these, AqB011, inhibits the AQP1 ion conductance (IC50 14 μM) at the intracellular loop D domains (Kourghi et al., 2016) involved in AQP1 ion channel gating. The figure shows docking of the bumetanide derivative AqB011 in the gating loop D domains (green) of the AQP1 tetrameric channel. The order of potency for AQP1 ion channel block matches the order for inhibition of cell migration, as well as in silico modeling of the predicted order of energetically favoured binding. Alternative medicines have proved to be another source of selective inhibitors of AQP1 that also impair cancer cell migration. Isolated from the Ayurvedic medicinal herb water hyssop (Bacopa monnieri), the AQP1-selective blockers bacopaside I and bacopaside II inhibit migration of AQP1-expressing HT29 colon cancer cells, with minimal effects on SW480 colon cancer cells that express little AQP1 (Pei et al., 2016). The presence of dual ion and water AQP1 channels in the leading edges of migrating cells is likely to facilitate local volume increases needed for protrusion. Combined inhibition of AQP1 water and ion fluxes is more powerful in arresting migration than either block alone. Blockers are reversible, selective, and non-toxic in migration-impairing dose ranges, and could be a useful adjunct for restraining metastasis in cancers that are dependent on AQP1 channels for motility.
Kourghi M, Pei JV, DeIeso ML, Flynn G, and Yool AJ. (2016). Bumetanide derivatives AqB007 and AqB011 selectively block the aquaporin-1 ion channel conductance and slow cancer cell migration. Mol Pharm 89: 133-140.
Pei JV, Kourghi M, DeIeso ML, Campbell EM, Doward HS, Hardingham JE, and Yool AJ. (2016). Differential inhibition of water and ion channel activities of mammalian Aquaporin-1 by two structurally related bacopaside compounds derived from the medicinal plant Bacopa monnieri. Mol Pharm 90: 496-507.