title: Rescue of the apoptotic-inducing function of mutant p53 by small molecule RITA.
abstract: Expression of mutant p53 correlates with poor prognosis in many tumors, therefore strategies aimed at reactivation of mutant p53 are likely to provide important benefits for treatment of tumors that are resistant to chemotherapy and radiotherapy. We have previously identified and characterized a small molecule RITA which binds p53 and induces a conformational change which prevents the binding of p53 to several inhibitors, including its own destructor MDM2. In this way, RITA rescues the tumor suppression function of wild type p53. Here, we demonstrate that RITA suppressed the growth and induced apoptosis in human tumor cell lines of a diverse origin carrying mutant p53 proteins. RITA restored transcriptional transactivation and transrepression function of several hot spot p53 mutants. The ability of RITA to rescue the activity of different p53 mutants suggests its generic mechanism of action. Thus, RITA is a promising lead for the development of anti-cancer drugs that reactivate the tumor suppressor function of p53 in cancer cells irrespective whether they express mutant or wild type p53.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Zhao
authors.forename: Vera V
authors.initials: VV
authors.lastname: Grinkevich
authors.forename: Fedor
authors.initials: F
authors.lastname: Nikulenkov
authors.forename: Wenjie
authors.initials: W
authors.lastname: Bao
authors.forename: Galina
authors.initials: G
authors.lastname: Selivanova
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005663:Furans / Q000627:therapeutic use*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005663:Furans; C118989:NSC 652287; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2