title: Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status.
abstract: Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness for preventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activity of silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used: RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates, genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 and miR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion, despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role of silibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.
authors.affiliation: Escola de Farmacia, Departamento de Analises Clinicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil.
authors.forename: Daiane Teixeira
authors.initials: DT
authors.lastname: DE Oliveira
authors.forename: Andre Luiz Ventura
authors.initials: AL
authors.lastname: Savio
authors.forename: Joao Paulo DE Castro
authors.initials: JP
authors.lastname: Marcondes
authors.forename: Tatiane Martins
authors.initials: TM
authors.lastname: Barros
authors.forename: Ludmila Correia
authors.initials: LC
authors.lastname: Barbosa
authors.forename: Daisy Maria Favero
authors.initials: DM
authors.lastname: Salvadori
authors.forename: Glenda Nicioli
authors.initials: GN
authors.lastname: DA Silva
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000096:biosynthesis; D000077385:Silybin; D012838:Silymarin / Q000008:administration & dosage* / Q000009:adverse effects; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: C544266:MIRN100 microRNA, human; D035683:MicroRNAs; D012838:Silymarin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000077385:Silybin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C546842:MTOR protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; C494921:AKT2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases