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dc.contributor.authorSavva, Christiana G.en
dc.contributor.authorTotokotsopoulos, S.en
dc.contributor.authorNicolaou, K. C.en
dc.contributor.authorNeophytou, Christiana M.en
dc.contributor.authorConstantinou, Andreas I.en
dc.date.accessioned2019-11-04T12:52:37Z
dc.date.available2019-11-04T12:52:37Z
dc.date.issued2016
dc.identifier.issn1471-2407
dc.identifier.urihttp://gnosis.library.ucy.ac.cy/handle/7/53368
dc.description.abstractBackground: Acquired resistance towards apoptosis is a hallmark of cancer. Elimination of cells bearing activated oncogenes or stimulation of tumor suppressor mediators may provide a selection pressure to overcome resistance. KC-53 is a novel biyouyanagin analogue known to elicit strong anti-inflammatory and anti-viral activity. The current study was designed to evaluate the anticancer efficacy and molecular mechanisms of KC-53 against human cancer cells. Methods: Using the MTT assay we examined initially how KC-53 affects the proliferation rates of thirteen representative human cancer cell lines in comparison to normal peripheral blood mononuclear cells (PBMCs) and immortalized cell lines. To decipher the key molecular events underlying its mode of action we selected the human promyelocytic leukemia HL-60 and the acute lymphocytic leukemia CCRF/CEM cell lines that were found to be the most sensitive to the antiproliferative effects of KC-53. Results: KC-53 promoted rapidly and irreversibly apoptosis in both leukemia cell lines at relatively low concentrations. Apoptosis was characterized by an increase in membrane-associated TNFR1, activation of Caspase-8 and proteolytic inactivation of the death domain kinase RIP1 indicating that KC-53 induced mainly the extrinsic/death receptor apoptotic pathway. Regardless, induction of the intrinsic/mitochondrial pathway was also achieved by Caspase-8 processing of Bid, activation of Caspase-9 and increased translocation of AIF to the nucleus. FADD protein knockdown restored HL-60 and CCRF/CEM cell viability and completely blocked KC-53-induced apoptosis. Furthermore, KC-53 administration dramatically inhibited TNFα-induced serine phosphorylation on TRAF2 and on IΚBα hindering therefore p65/NF-ΚΒ translocation to nucleus. Reduced transcriptional expression of pro-inflammatory and pro-survival p65 target genes, confirmed that the agent functionally inhibited the transcriptional activity of p65. Conclusions: Our findings demonstrate, for the first time, the selective anticancer properties of KC-53 towards leukemic cell lines and provide a detailed understanding of the molecular events underlying its dual anti-proliferative and pro-apoptotic properties. These results provide new insights into the development of innovative and targeted therapies for the treatment of some forms of leukemia. © 2016 Savva et al.en
dc.sourceBMC Canceren
dc.source.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84964374900&doi=10.1186%2fs12885-016-2310-5&partnerID=40&md5=0300be467f9fedd2a3c0c07e723fb41c
dc.subjectNF-ΚΒel
dc.subjectNuclear factor ΚΒel
dc.subjectantineoplastic agenten
dc.subjecthumanen
dc.subjectHumansen
dc.subjectcontrolled studyen
dc.subjectdrug efficacyen
dc.subjectcell proliferationen
dc.subjectunclassified drugen
dc.subjectgene expression regulationen
dc.subjectimmunoglobulin enhancer binding proteinen
dc.subjectpathologyen
dc.subjectsignal transductionen
dc.subjectArticleen
dc.subjectApoptosisen
dc.subjecthuman cellen
dc.subjectbiosynthesisen
dc.subjectgeneticsen
dc.subjecttumor necrosis factor alphaen
dc.subjectNeoplasm Proteinsen
dc.subjectLeukemiaen
dc.subjectmononuclear cellen
dc.subjectchemistryen
dc.subjectdrug effectsen
dc.subjectCaspasesen
dc.subjectleukemia cell lineen
dc.subjectphosphorylationen
dc.subjectcellular distributionen
dc.subjectperipheral blood mononuclear cellen
dc.subjectcell viabilityen
dc.subjectHL-60 Cellsen
dc.subjectcaspase 9en
dc.subjectNF-kappa Ben
dc.subjectprotein phosphorylationen
dc.subjectapoptosis inducing factoren
dc.subjectMitochondriaen
dc.subjectmitochondrionen
dc.subjectprotein Biden
dc.subjectLeukocytes, Mononuclearen
dc.subjectGene Expression Regulation, Neoplasticen
dc.subjectcaspase 8en
dc.subjectcell nucleusen
dc.subjectantiproliferative activityen
dc.subjectbinding proteinen
dc.subjectBiyouyanaginen
dc.subjectbiyouyanagin Aen
dc.subjectDeath receptorsen
dc.subjectFas associated death domain proteinen
dc.subjectHL 60 cell lineen
dc.subjectHL-60 cell lineen
dc.subjectI kappa B alphaen
dc.subjectimmortalized cell lineen
dc.subjectkc 53en
dc.subjectreceptor interacting protein 1en
dc.subjectReceptors, Tumor Necrosis Factor, Type Ien
dc.subjectsesquiterpeneen
dc.subjectsesquiterpene lactoneen
dc.subjectSesquiterpenesen
dc.subjectspiro compounden
dc.subjectSpiro Compoundsen
dc.subjectTNFR1en
dc.subjecttranscription factor RelAen
dc.subjectTumor necrosis factor receptor 1en
dc.subjecttumor necrosis factor receptor associated factor 2en
dc.subjecttumor proteinen
dc.titleSelective activation of TNFR1 and NF-ΚB inhibition by a novel biyouyanagin analogue promotes apoptosis in acute leukemia cellsen
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1186/s12885-016-2310-5
dc.description.volume16
dc.type.uhtypeArticleen
dc.description.notes<p>Cited By :1</p>en
dc.source.abbreviationBMC Canceren
dc.contributor.orcidConstantinou, Andreas I. [0000-0003-0365-1821]


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