{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T04:02:59Z","timestamp":1768881779845,"version":"3.49.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T00:00:00Z","timestamp":1555027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>AqB013 and AqB050 compounds inhibit aquaporin 1 (AQP1), a dual water and ion channel implicated in tumour angiogenesis. We tested AqB013 and AqB050 either as monotherapy or in combination on tube formation of murine endothelial cells (2H-11 and 3B-11) and human umbilical vascular endothelial cells (HUVECs). The mechanism underlying their anti-tubulogenic effect was explored by examining cell viability, induction of apoptosis and migration using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, Annexin V\/propidium iodide apoptosis assay and scratch wound assay. Tube formation of all the cell lines was inhibited by AqB013, AqB050 and the combination of the two compounds. The inhibition of 2H-11 and 3B-11 was frequently accompanied by impaired migration, whereas that of HUVEC treated with AqB050 and the combination was associated with reduced cell viability due to apoptosis. AqB013 and AqB050 exhibited an anti-tubulogenic effect through inhibition of AQP1-mediated cell migration and induction of apoptosis. Together with previously reported anti-tumour cell effect of AqB013 and AqB050, our findings support further evaluation of these compounds as potential cancer therapeutics.<\/jats:p>","DOI":"10.3390\/ijms20081818","type":"journal-article","created":{"date-parts":[[2019,4,12]],"date-time":"2019-04-12T12:55:04Z","timestamp":1555073704000},"page":"1818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Bumetanide-Derived Aquaporin 1 Inhibitors, AqB013 and AqB050 Inhibit Tube Formation of Endothelial Cells through Induction of Apoptosis and Impaired Migration In Vitro"],"prefix":"10.3390","volume":"20","author":[{"given":"Yoko","family":"Tomita","sequence":"first","affiliation":[{"name":"Solid Tumour Group, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Medical Oncology, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3803-5113","authenticated-orcid":false,"given":"Helen M.","family":"Palethorpe","sequence":"additional","affiliation":[{"name":"Solid Tumour Group, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2958-3492","authenticated-orcid":false,"given":"Eric","family":"Smith","sequence":"additional","affiliation":[{"name":"Solid Tumour Group, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5357-7167","authenticated-orcid":false,"given":"Maryam","family":"Nakhjavani","sequence":"additional","affiliation":[{"name":"Solid Tumour Group, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda R.","family":"Townsend","sequence":"additional","affiliation":[{"name":"Solid Tumour Group, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Medical Oncology, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy J.","family":"Price","sequence":"additional","affiliation":[{"name":"Solid Tumour Group, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"},{"name":"Medical Oncology, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1283-585X","authenticated-orcid":false,"given":"Andrea J.","family":"Yool","sequence":"additional","affiliation":[{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8277-1199","authenticated-orcid":false,"given":"Jennifer E.","family":"Hardingham","sequence":"additional","affiliation":[{"name":"Solid Tumour Group, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, SA 5011, Australia"},{"name":"Adelaide Medical School, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.pmch.2014.11.002","article-title":"Recent advances in cancer therapeutics","volume":"54","author":"Chessum","year":"2015","journal-title":"Prog. Med. Chem."},{"key":"ref_3","first-page":"F463","article-title":"Aquaporin CHIP: The archetypal molecular water channel","volume":"265","author":"Agre","year":"1993","journal-title":"Am. J. Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"15634","DOI":"10.1016\/S0021-9258(19)37635-5","article-title":"Identification, purification, and partial characterization of a novel Mr 28,000 integral membrane protein from erythrocytes and renal tubules","volume":"263","author":"Denker","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1126\/science.273.5279.1216","article-title":"Forskolin stimulation of water and cation permeability in aquaporin 1 water channels","volume":"273","author":"Yool","year":"1996","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1124\/mol.57.3.576","article-title":"Cloned human aquaporin-1 is a cyclic GMP-gated ion channel","volume":"57","author":"Anthony","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Tomita, Y., Hilary, D., Andrea, J.Y., Eric, S., Amanda, R.T., Timothy, J.P., and Jennifer, E.H. (2017). Role of aquaporin 1 signalling in cancer development and progression. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18020299"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/nrd4226","article-title":"Aquaporins: Important but elusive drug targets","volume":"13","author":"Verkman","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1006\/mvre.1999.2158","article-title":"Water channel (aquaporin 1) expression and distribution in mammary carcinomas and glioblastomas","volume":"58","author":"Endo","year":"1999","journal-title":"Microvasc. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/sj.bjc.6600512","article-title":"Increased aquaporin 1 water channel expression in human brain tumours","volume":"87","author":"Saadoun","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6699","DOI":"10.1038\/sj.onc.1206762","article-title":"Involvement of aquaporins in colorectal carcinogenesis","volume":"22","author":"Moon","year":"2003","journal-title":"Oncogene"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.2353\/ajpath.2006.050596","article-title":"Aquaporin 1 is overexpressed in lung cancer and stimulates NIH-3T3 cell proliferation and anchorage-independent growth","volume":"168","author":"Hoque","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_13","first-page":"511","article-title":"Expression of aquaporin-1 in nasopharyngeal cancer tissues","volume":"39","author":"Li","year":"2010","journal-title":"J. Otolaryngol. Head Neck Surg."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chen, R., Shi, Y., Amiduo, R., Tuokan, T., and Suzuk, L. (2014). Expression and prognostic value of aquaporin 1, 3 in cervical carcinoma in women of Uygur ethnicity from Xinjiang, China. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098576"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3973","DOI":"10.7314\/APJCP.2015.16.9.3973","article-title":"Expression of aquaporin 1 in bladder uroepithelial cell carcinoma and its relevance to recurrence","volume":"16","author":"Liu","year":"2015","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s12253-016-0145-7","article-title":"Overexpression of aquaporin-1 is a prognostic factor for biochemical recurrence in prostate adenocarcinoma","volume":"23","author":"Park","year":"2016","journal-title":"Pathol. Oncol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13046-016-0310-6","article-title":"Pharmacological blockade of aquaporin-1 water channel by AqB013 restricts migration and invasiveness of colon cancer cells and prevents endothelial tube formation in vitro","volume":"35","author":"Dorward","year":"2016","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1146\/annurev.med.49.1.407","article-title":"Angiogenesis and tumor metastasis","volume":"49","author":"Zetter","year":"1998","journal-title":"Annu. Rev. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1038\/nature03460","article-title":"Impairment of angiogenesis and cell migration by targeted aquaporin-1 gene disruption","volume":"434","author":"Saadoun","year":"2005","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s00109-012-0977-x","article-title":"Inhibition of aquaporin-1 dependent angiogenesis impairs tumour growth in a mouse model of melanoma","volume":"91","author":"Nicchia","year":"2013","journal-title":"J. Mol. Med. (Berl.)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1096\/fj.13-245621","article-title":"Aquaporin-1 gene deletion reduces breast tumor growth and lung metastasis in tumor-producing MMTV-PyVT mice","volume":"28","author":"Jin","year":"2014","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1124\/mol.108.053744","article-title":"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","volume":"76","author":"Migliati","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Palethorpe, H.M., Tomita, Y., Smith, E., Pei, J.V., Townsend, A.R., Price, T.J., Young, J.P., Yool, A.J., and Hardingham, J.E. (2018). The aquaporin 1 inhibitor bacopaside II reduces endothelial cell migration and tubulogenesis and induces apoptosis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030653"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.virol.2008.11.024","article-title":"SV40: Cell transformation and tumorigenesis","volume":"384","author":"Pipas","year":"2009","journal-title":"Virology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7729","DOI":"10.1038\/sj.onc.1209046","article-title":"SV40 large T antigen targets multiple cellular pathways to elicit cellular transformation","volume":"24","author":"Ahuja","year":"2005","journal-title":"Oncogene"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1080\/15384047.2015.1070983","article-title":"RNAi-mediated silencing of AQP1 expression inhibited the proliferation, invasion and tumorigenesis of osteosarcoma cells","volume":"16","author":"Wu","year":"2015","journal-title":"Cancer Biol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1111\/jcmm.13378","article-title":"Aquaporin-1 inhibition reduces metastatic formation in a mouse model of melanoma","volume":"22","author":"Simone","year":"2018","journal-title":"J. Cell. Mol. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1159\/000443843","article-title":"Expression of AQP1 was associated with apoptosis and survival of patients in gastric adenocarcinoma","volume":"33","author":"Sun","year":"2016","journal-title":"Dig. Surg."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"C975","DOI":"10.1152\/ajpcell.00180.2003","article-title":"Plasma membrane aquaporin activity can affect the rate of apoptosis but is inhibited after apoptotic volume decrease","volume":"286","author":"Jablonski","year":"2004","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"20130104","DOI":"10.1098\/rstb.2013.0104","article-title":"Ion channels and apoptosis in cancer","volume":"369","author":"Bortner","year":"2014","journal-title":"Philos. Trans. R. Soc. Lond. B Biol. Sci."},{"key":"ref_31","first-page":"68","article-title":"New roles for old holes: Ion channel function in aquaporin-1","volume":"17","author":"Yool","year":"2002","journal-title":"News Physiol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Monzani, E., Bazzotti, R., Perego, C., and La Porta, C.A. (2009). AQP1 is not only a water channel: It contributes to cell migration through Lin7\/beta-catenin. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006167"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.3892\/or.2015.4107","article-title":"Aquaporin 1 promotes the proliferation and migration of lung cancer cell in vitro","volume":"34","author":"Wei","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1002\/iub.243","article-title":"Aquaporin-1 activity of plasma membrane affects HT20 colon cancer cell migration","volume":"61","author":"Jiang","year":"2009","journal-title":"IUBMB Life"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1124\/mol.115.101618","article-title":"Bumetanide derivatives AqB007 and AqB011 selectively block the aquaporin-1 ion channel conductance and slow cancer cell migration","volume":"89","author":"Kourghi","year":"2016","journal-title":"Mol. Pharimacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"286719","DOI":"10.1155\/2015\/286719","article-title":"Blockade of aquaporin 1 inhibits proliferation, motility, and metastatic potential of mesothelioma in vitro but not in an in vivo model","volume":"2015","author":"Klebe","year":"2015","journal-title":"Dis. Markers"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Smith, E., Palethorpe, H.M., Tomita, Y., Pei, J.V., Townsend, A.R., Price, T.J., Young, J.P., Yool, A.J., and Hardingham, J.E. (2018). The purified extract from the medicinal plant Bacopa monnieri, bacopaside ii, inhibits growth of colon cancer cells in vitro by inducing cell cycle arrest and apoptosis. Cells, 7.","DOI":"10.3390\/cells7070081"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/8\/1818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:44:59Z","timestamp":1760186699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/8\/1818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,12]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20081818"],"URL":"https:\/\/doi.org\/10.3390\/ijms20081818","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,12]]}}}