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dc.contributor.authorMacCallum, Stephanie F.
dc.contributor.authorGroves, Michael J.
dc.contributor.authorJames, John
dc.contributor.authorMurray, Karen
dc.contributor.authorAppleyard, Virginia
dc.contributor.authorPrescott, Alan R.
dc.contributor.authorDrbal, Abed A.
dc.contributor.authorNicolaou, Anna
dc.contributor.authorCunningham, Joan
dc.contributor.authorHaydock, Sally
dc.contributor.authorGanley, Ian G.
dc.contributor.authorWestwood, Nicholas J.
dc.contributor.authorCoates, Philip J.
dc.contributor.authorLain, Sonia
dc.contributor.authorTauro, Sudhir
dc.date.accessioned2014-07-21T11:01:06Z
dc.date.available2014-07-21T11:01:06Z
dc.date.issued2013-02-14
dc.identifier134131875
dc.identifier33b8fed0-471c-4e04-b240-a3401aef708d
dc.identifier000314864800003
dc.identifier84874339014
dc.identifier.citationMacCallum , S F , Groves , M J , James , J , Murray , K , Appleyard , V , Prescott , A R , Drbal , A A , Nicolaou , A , Cunningham , J , Haydock , S , Ganley , I G , Westwood , N J , Coates , P J , Lain , S & Tauro , S 2013 , ' Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6 ' , Scientific Reports , vol. 3 , 1275 . https://doi.org/10.1038/srep01275en
dc.identifier.issn2045-2322
dc.identifier.otherORCID: /0000-0003-0630-0138/work/56424165
dc.identifier.urihttps://hdl.handle.net/10023/5043
dc.descriptionThe authors acknowledge TENOVUS Tayside for funding the studyen
dc.description.abstractTenovin-6 (Tnv-6) is a bioactive small molecule with anti-neoplastic activity. Inhibition of the Sirtuin class of protein deacetylases with activation of p53 function is associated with the pro-apoptotic effects of Tnv-6 in many tumors. Here, we demonstrate that in chronic lymphocytic leukemia (CLL) cells, Tnv-6 causes non-genotoxic cytotoxicity, without adversely affecting human clonogenic hematopoietic progenitors in vitro, or murine hematopoiesis. Mechanistically, exposure of CLL cells to Tnv-6 did not induce cellular apoptosis or p53-pathway activity. Transcriptomic profiling identified a gene program influenced by Tnv-6 that included autophagy-lysosomal pathway genes. The dysregulation of autophagy was confirmed by changes in cellular ultrastructure and increases in the autophagy-regulatory proteins LC3 (LC3-II) and p62/Sequestosome. Adding bafilomycin-A1, an autophagy inhibitor to Tnv-6 containing cultures did not cause synergistic accumulation of LC3-II, suggesting inhibition of late-stage autophagy by Tnv-6. Thus, in CLL, the cytotoxic effects of Tnv-6 result from dysregulation of protective autophagy pathways.
dc.format.extent8
dc.format.extent1253117
dc.language.isoeng
dc.relation.ispartofScientific Reportsen
dc.subjectHistone deacetylaseen
dc.subjectCell-deathen
dc.subjectElectron-microscopyen
dc.subjectPromote longevityen
dc.subjectStress responseen
dc.subjectTP53 mutationen
dc.subjectIn-vivoen
dc.subjectP53en
dc.subjectFludarabineen
dc.subjectActivationen
dc.subjectR Medicineen
dc.subject.lccRen
dc.titleDysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6en
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. School of Chemistryen
dc.contributor.institutionUniversity of St Andrews. EaSTCHEMen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.identifier.doi10.1038/srep01275
dc.description.statusPeer revieweden
dc.identifier.urlhttp://www.nature.com/srep/2013/130214/srep01275/extref/srep01275-s2.xlsen
dc.identifier.urlhttp://www.nature.com/srep/2013/130214/srep01275/extref/srep01275-s1.pdfen


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