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dc.contributor.authorMeehan, James
dc.contributor.authorWard, Carol
dc.contributor.authorTurnbull, Arran
dc.contributor.authorBukowski-Wills, Jimi
dc.contributor.authorFinch, Andrew
dc.contributor.authorJarman, Edward J.
dc.contributor.authorXintaropoulou, Chrysi
dc.contributor.authorMartinez-Perez, Carlos
dc.contributor.authorGray, Mark
dc.contributor.authorPearson, Matthew
dc.contributor.authorMullen, Peter
dc.contributor.authorSupuran, Claudia T.
dc.contributor.authorCarta, Fabrizio
dc.contributor.authorHarrison, David James
dc.contributor.authorKunkler, Ian H.
dc.contributor.authorLangdon, Simon
dc.identifier.citationMeehan , J , Ward , C , Turnbull , A , Bukowski-Wills , J , Finch , A , Jarman , E J , Xintaropoulou , C , Martinez-Perez , C , Gray , M , Pearson , M , Mullen , P , Supuran , C T , Carta , F , Harrison , D J , Kunkler , I H & Langdon , S 2017 , ' Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells ' , Oncotarget , vol. 8 , no. 26 , pp. 42857-42875 .
dc.identifier.otherPURE: 249397341
dc.identifier.otherPURE UUID: 7882e747-077c-4965-8910-51e0523a365e
dc.identifier.otherScopus: 85021273991
dc.identifier.otherWOS: 000405493400090
dc.identifier.otherORCID: /0000-0001-9041-9988/work/64034235
dc.descriptionThe following organizations are gratefully acknowledged: University of Edinburgh (JM), Medical Research Council (EJJ), EPSRC IMPACT (CW), Medical Research Scotland (CX) and Scottish Universities Life Sciences Alliance (CMP). This research was financed in part by a Grant of the 7th Framework Program of the European Union (METOXIA project; HEALTH-F2-2009-222741), along with the Breast Cancer Institute (BCI) and Aitken Breast Cancer Research Fund.en
dc.description.abstractHypoxic cancer cells exhibit resistance to many therapies. This study compared the therapeutic effect of targeting the pH regulatory proteins (CAIX, NHE1 and V-ATPase) that permit cancer cells to adapt to hypoxic conditions, using both 2D and 3D culture models. Drugs targeting CAIX, NHE1 and V-ATPase exhibited anti-proliferative effects in MCF-7, MDA-MB-231 and HBL-100 breast cancer cell lines in 2D. Protein and gene expression analysis in 2D showed that CAIX was the most hypoxia-inducible protein of the 3 targets. However, the expression of CAIX differed between the 3 cell lines. This difference in CAIX expression in hypoxia was consistent with a varying activity of FIH-1 between the cell lines. 3D expression analysis demonstrated that both CAIX and NHE1 were up-regulated in the hypoxic areas of multicellular tumor spheroids. However, the induction of CAIX expression in hypoxia was again cell line dependent. 3D invasion assays conducted with spheroids showed that CAIX inhibition significantly reduced the invasion of cells. Finally, the capability of both NHE1 and CAIX inhibitors to combine effectively with irradiation was exhibited in clonogenic assays. Proteomic-mass-spectrometric analysis indicated that CAIX inhibition might be combining with irradiation through stimulating apoptotic cell death. Of the three proteins, CAIX represents the target with the most promise for the treatment of breast cancer.
dc.rightsThis is an open access article, licensed under a Creative Commons Attribution 3.0 License (
dc.subjectCarbonic anhydrase IXen
dc.subjectBreast canceren
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectRM Therapeutics. Pharmacologyen
dc.subjectSDG 3 - Good Health and Well-beingen
dc.titleInhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cellsen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.contributor.institutionUniversity of St Andrews. Cellular Medicine Divisionen
dc.description.statusPeer revieweden

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