title: PRIMA-1 induces caspase-mediated apoptosis in acute promyelocytic leukemia NB4 cells by inhibition of nuclear factor-κB and downregulation of Bcl-2, XIAP, and c-Myc.
abstract: Restoration of p53 function triggers cell death and eliminates tumors in vivo. Identification of p53-reactivating small molecules such as PRIMA-1 holds promise for effective new anticancer therapies. Here, we investigated the effects of small molecule PRIMA-1 on cell viability and expression of p53-regulated genes and proteins in the acute promyelocytic leukemia-derived NB4 cell line. Our results showed that PRIMA-1 had antileukemic properties in acute promyelocytic leukemia-derived NB4 cells. PRIMA-1-triggered apoptosis in a dose-dependent and time-dependent manner as indicated by the MTT assay and annexin-V staining. Apoptosis induction by PRIMA-1 was associated with caspase-9, caspase-7 activation and PARP cleavage. p21 protein expression was increased after PRIMA-1 treatment and real-time PCR analysis of proapoptotic p53 target genes indicated upregulation of Bax and Noxa. Western blot analysis showed that IκBα phosphorylation and its degradation were inhibited by PRIMA-1. Moreover, protein expression of nuclear factor-κB-regulated antiapoptotic (Bcl-2 and XIAP) and proliferative (c-Myc) gene products was decreased. Importantly, PRIMA-1 did not show any significant apoptotic effect in normal human peripheral blood mononuclear cells. These in-vitro studies imply that p53 reactivation by small compounds may become a novel anticancer therapy in acute promyelocytic leukemia.
authors.affiliation: aDepartment of Hematology and Blood Banking, Faculty of Allied Medicine bCellular and Molecular Research Center cDepartment of Pharmacology, School of Medicine, Iran University of Medical Sciences dDepartment of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Elham
authors.initials: E
authors.lastname: Farhadi
authors.forename: Majid
authors.initials: M
authors.lastname: Safa
authors.forename: Ali M
authors.initials: AM
authors.lastname: Sharifi
authors.forename: Davood
authors.initials: D
authors.lastname: Bashash
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001372:Aza Compounds / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
chemical_list: D001372:Aza Compounds; C000595707:BCL2 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C489427:MYC protein, human; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C509186:TERT protein, human; D019098:Telomerase; C451219:2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one