Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Pharmacol
2015 Jan 14;891:133-40. doi: 10.1124/mol.115.101618.
Show Gene links
Show Anatomy links
Bumetanide Derivatives AqB007 and AqB011 Selectively Block the Aquaporin-1 Ion Channel Conductance and Slow Cancer Cell Migration.
Kourghi M, Pei JV, De Ieso ML, Flynn G, Yool AJ.
???displayArticle.abstract???
Aquaporins (AQPs) in the major intrinsic family of proteins mediate fluxes of water and other small solutes across cell membranes. AQP1 is a water channel, and under permissive conditions, a nonselective cation channel gated by cGMP. In addition to mediating fluid transport, AQP1 expression facilitates rapid cell migration in cell types including colon cancers and glioblastoma. Work here defines new pharmacological derivatives of bumetanide that selectively inhibit the ion channel, but not the water channel, activity of AQP1. Human AQP1 was analyzed in the Xenopus laevis oocyte expression system by two-electrode voltage clamp and optical osmotic swelling assays. The aquaporin ligand bumetanide derivative AqB011 was the most potent blocker of the AQP1 ion conductance (IC50 of 14 μM), with no effect on water channel activity (at up to 200 μM). The order of potency for inhibition of the ionic conductance was AqB011 > AqB007 > AqB006 ≥ AqB001. Migration of human colon cancer (HT29) cells was assessed with a wound-closure assay in the presence of a mitotic inhibitor. AqB011 and AqB007 significantly reduced migration rates of AQP1-positive HT29 cells without affecting viability. The order of potency for AQP1 ion channel block matched the order for inhibition of cell migration, as well as in silico modeling of the predicted order of energetically favored binding. Docking models suggest that AqB011 and AqB007 interact with the intracellular loop D domain, a region involved in AQP channel gating. Inhibition of AQP1 ionic conductance could be a useful adjunct therapeutic approach for reducing metastasis in cancers that upregulate AQP1 expression.
Agre,
Aquaporin CHIP: the archetypal molecular water channel.
1993, Pubmed,
Xenbase
Agre,
Aquaporin CHIP: the archetypal molecular water channel.
1993,
Pubmed
,
Xenbase Anthony,
Cloned human aquaporin-1 is a cyclic GMP-gated ion channel.
2000,
Pubmed
,
Xenbase Arnaoutova,
Aquaporin 1 is important for maintaining secretory granule biogenesis in endocrine cells.
2008,
Pubmed Baetz,
Role of aquaporin-1 in trabecular meshwork cell homeostasis during mechanical strain.
2009,
Pubmed Boassa,
Single amino acids in the carboxyl terminal domain of aquaporin-1 contribute to cGMP-dependent ion channel activation.
2003,
Pubmed
,
Xenbase Boassa,
Ion channel function of aquaporin-1 natively expressed in choroid plexus.
2006,
Pubmed Brooks,
Inhibition of aquaporin-1 water permeability by tetraethylammonium: involvement of the loop E pore region.
2000,
Pubmed
,
Xenbase Campbell,
Invertebrate aquaporins: a review.
2008,
Pubmed Campbell,
The activity of human aquaporin 1 as a cGMP-gated cation channel is regulated by tyrosine phosphorylation in the carboxyl-terminal domain.
2012,
Pubmed
,
Xenbase Chen,
WiDr is a derivative of another colon adenocarcinoma cell line, HT-29.
1987,
Pubmed Detmers,
Quaternary ammonium compounds as water channel blockers. Specificity, potency, and site of action.
2006,
Pubmed El Hindy,
Correlation of aquaporin-1 water channel protein expression with tumor angiogenesis in human astrocytoma.
2013,
Pubmed Finn,
The lineage-specific evolution of aquaporin gene clusters facilitated tetrapod terrestrial adaptation.
2014,
Pubmed Fu,
Structure of a glycerol-conducting channel and the basis for its selectivity.
2000,
Pubmed Hara-Chikuma,
Aquaporin-1 facilitates epithelial cell migration in kidney proximal tubule.
2006,
Pubmed Hu,
Increased migration and metastatic potential of tumor cells expressing aquaporin water channels.
2006,
Pubmed Huber,
Identification of aquaporin 4 inhibitors using in vitro and in silico methods.
2009,
Pubmed Ishibashi,
New members of mammalian aquaporins: AQP10-AQP12.
2009,
Pubmed Jiang,
Aquaporin-1 activity of plasma membrane affects HT20 colon cancer cell migration.
2009,
Pubmed Jung,
Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance.
1994,
Pubmed
,
Xenbase McCoy,
Expression and function of water channels (aquaporins) in migrating malignant astrocytes.
2007,
Pubmed Migliati,
Inhibition of aquaporin-1 and aquaporin-4 water permeability by a derivative of the loop diuretic bumetanide acting at an internal pore-occluding binding site.
2009,
Pubmed
,
Xenbase Monzani,
The water channels, new druggable targets to combat cancer cell survival, invasiveness and metastasis.
2007,
Pubmed Nicchia,
Inhibition of aquaporin-1 dependent angiogenesis impairs tumour growth in a mouse model of melanoma.
2013,
Pubmed Oshio,
Impaired pain sensation in mice lacking Aquaporin-1 water channels.
2006,
Pubmed Park,
Phylogenetic characterization of the MIP family of transmembrane channel proteins.
1996,
Pubmed Preston,
The mercury-sensitive residue at cysteine 189 in the CHIP28 water channel.
1993,
Pubmed
,
Xenbase Preston,
Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein.
1992,
Pubmed
,
Xenbase Reizer,
The MIP family of integral membrane channel proteins: sequence comparisons, evolutionary relationships, reconstructed pathway of evolution, and proposed functional differentiation of the two repeated halves of the proteins.
1993,
Pubmed Saparov,
Water and ion permeation of aquaporin-1 in planar lipid bilayers. Major differences in structural determinants and stoichiometry.
2001,
Pubmed Schwab,
Cells move when ions and water flow.
2007,
Pubmed Seeliger,
Discovery of novel human aquaporin-1 blockers.
2013,
Pubmed
,
Xenbase Søgaard,
Test of blockers of AQP1 water permeability by a high-resolution method: no effects of tetraethylammonium ions or acetazolamide.
2008,
Pubmed
,
Xenbase Sui,
Structural basis of water-specific transport through the AQP1 water channel.
,
Pubmed Trott,
AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.
2010,
Pubmed Tsunoda,
Aquaporin-1, nothing but a water channel.
2004,
Pubmed
,
Xenbase Yool,
AqF026 is a pharmacologic agonist of the water channel aquaporin-1.
2013,
Pubmed
,
Xenbase Yool,
Structure, function and translational relevance of aquaporin dual water and ion channels.
2012,
Pubmed Yool,
Roles for novel pharmacological blockers of aquaporins in the treatment of brain oedema and cancer.
2010,
Pubmed Yool,
Forskolin stimulation of water and cation permeability in aquaporin 1 water channels.
1996,
Pubmed
,
Xenbase Yool,
Functional domains of aquaporin-1: keys to physiology, and targets for drug discovery.
2007,
Pubmed Yoshida,
Expression of aquaporin-1 is a poor prognostic factor for stage II and III colon cancer.
2013,
Pubmed Yu,
Mechanism of gating and ion conductivity of a possible tetrameric pore in aquaporin-1.
2006,
Pubmed Zhang,
Aquaporin-1 channel function is positively regulated by protein kinase C.
2007,
Pubmed
,
Xenbase Zhang,
Aquaporin-1 water permeability as a novel determinant of axonal regeneration in dorsal root ganglion neurons.
2015,
Pubmed
