dc.contributor.author | Savva, Christiana G. | en |
dc.contributor.author | Totokotsopoulos, S. | en |
dc.contributor.author | Nicolaou, K. C. | en |
dc.contributor.author | Neophytou, Christiana M. | en |
dc.contributor.author | Constantinou, Andreas I. | en |
dc.creator | Savva, Christiana G. | en |
dc.creator | Totokotsopoulos, S. | en |
dc.creator | Nicolaou, K. C. | en |
dc.creator | Neophytou, Christiana M. | en |
dc.creator | Constantinou, Andreas I. | en |
dc.date.accessioned | 2019-11-04T12:52:37Z | |
dc.date.available | 2019-11-04T12:52:37Z | |
dc.date.issued | 2016 | |
dc.identifier.issn | 1471-2407 | |
dc.identifier.uri | http://gnosis.library.ucy.ac.cy/handle/7/53368 | |
dc.description.abstract | Background: 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.source | BMC Cancer | en |
dc.source.uri | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84964374900&doi=10.1186%2fs12885-016-2310-5&partnerID=40&md5=0300be467f9fedd2a3c0c07e723fb41c | |
dc.subject | NF-ΚΒ | el |
dc.subject | Nuclear factor ΚΒ | el |
dc.subject | antineoplastic agent | en |
dc.subject | human | en |
dc.subject | Humans | en |
dc.subject | controlled study | en |
dc.subject | drug efficacy | en |
dc.subject | cell proliferation | en |
dc.subject | unclassified drug | en |
dc.subject | gene expression regulation | en |
dc.subject | immunoglobulin enhancer binding protein | en |
dc.subject | pathology | en |
dc.subject | signal transduction | en |
dc.subject | Article | en |
dc.subject | Apoptosis | en |
dc.subject | human cell | en |
dc.subject | biosynthesis | en |
dc.subject | genetics | en |
dc.subject | tumor necrosis factor alpha | en |
dc.subject | Neoplasm Proteins | en |
dc.subject | Leukemia | en |
dc.subject | mononuclear cell | en |
dc.subject | chemistry | en |
dc.subject | drug effects | en |
dc.subject | Caspases | en |
dc.subject | leukemia cell line | en |
dc.subject | phosphorylation | en |
dc.subject | cellular distribution | en |
dc.subject | peripheral blood mononuclear cell | en |
dc.subject | cell viability | en |
dc.subject | HL-60 Cells | en |
dc.subject | caspase 9 | en |
dc.subject | NF-kappa B | en |
dc.subject | protein phosphorylation | en |
dc.subject | apoptosis inducing factor | en |
dc.subject | Mitochondria | en |
dc.subject | mitochondrion | en |
dc.subject | protein Bid | en |
dc.subject | Leukocytes, Mononuclear | en |
dc.subject | Gene Expression Regulation, Neoplastic | en |
dc.subject | caspase 8 | en |
dc.subject | cell nucleus | en |
dc.subject | antiproliferative activity | en |
dc.subject | binding protein | en |
dc.subject | Biyouyanagin | en |
dc.subject | biyouyanagin A | en |
dc.subject | Death receptors | en |
dc.subject | Fas associated death domain protein | en |
dc.subject | HL 60 cell line | en |
dc.subject | HL-60 cell line | en |
dc.subject | I kappa B alpha | en |
dc.subject | immortalized cell line | en |
dc.subject | kc 53 | en |
dc.subject | receptor interacting protein 1 | en |
dc.subject | Receptors, Tumor Necrosis Factor, Type I | en |
dc.subject | sesquiterpene | en |
dc.subject | sesquiterpene lactone | en |
dc.subject | Sesquiterpenes | en |
dc.subject | spiro compound | en |
dc.subject | Spiro Compounds | en |
dc.subject | TNFR1 | en |
dc.subject | transcription factor RelA | en |
dc.subject | Tumor necrosis factor receptor 1 | en |
dc.subject | tumor necrosis factor receptor associated factor 2 | en |
dc.subject | tumor protein | en |
dc.title | Selective activation of TNFR1 and NF-ΚB inhibition by a novel biyouyanagin analogue promotes apoptosis in acute leukemia cells | en |
dc.type | info:eu-repo/semantics/article | |
dc.identifier.doi | 10.1186/s12885-016-2310-5 | |
dc.description.volume | 16 | |
dc.author.faculty | Σχολή Θετικών και Εφαρμοσμένων Επιστημών / Faculty of Pure and Applied Sciences | |
dc.author.department | Τμήμα Βιολογικών Επιστημών / Department of Biological Sciences | |
dc.type.uhtype | Article | en |
dc.description.notes | <p>Cited By :1</p> | en |
dc.source.abbreviation | BMC Cancer | en |
dc.contributor.orcid | Constantinou, Andreas I. [0000-0003-0365-1821] | |
dc.gnosis.orcid | 0000-0003-0365-1821 | |