title: RETRA exerts anticancer activity in Ewing's sarcoma cells independent of their TP53 status.
abstract: Mutant p53 can exert oncogenic activity by inhibitory interaction with p73. The small-molecule RETRA has been described to disrupt this interaction and to suppress carcinoma cells (Kravchenko et al., 2008). RETRA's anticancer activity was restricted to tumour cells bearing mutant p53; it was not active in p53 negative and in p53 wild-type cells. Here, we explored the responsiveness of Ewing's sarcoma (ES) cells with mutant p53 to RETRA. For comparison, we also tested RETRA in p53 null and in p53 wild-type ES cells. We found RETRA to be effective in the three mutant p53 ES cell lines investigated. Strikingly, however, RETRA was similarly effective in the p53-deficient and in the two p53 wild-type ES cell lines examined. RETRA elicited apoptosis, as assessed by flow cytometric analyses of mitochondrial depolarisation and DNA fragmentation, caspase 3/7 activity assay and PARP-1 cleavage immunodetection, and G2/M cell cycle arrest completely independent of the cellular TP53 status. In contrast, various p53-deficient and -proficient carcinoma, osteosarcoma and leukaemia cells were unresponsive to RETRA. RETRA also induced gene expression of p53 target genes PUMA and p21 in ES cells irrespective of their TP53 status. These in vitro findings provide a rationale for an in vivo exploration of RETRA's potential as an effective therapeutic approach for patients with ES.
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany. Electronic address: juergen.sonnemann@med.uni-jena.de.
authors: Jürgen
authors: J
authors: Sonnemann
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
authors: Désirée
authors: D
authors: Grauel
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
authors: Lisa
authors: L
authors: Blümel
authors: CF Centre, Children's Clinic, Jena University Hospital, Jena, Germany; Institute of Human Genetics, University Hospital of Leipzig, Leipzig, Germany.
authors: Julia
authors: J
authors: Hentschel
authors: Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany.
authors: Christian
authors: C
authors: Marx
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
authors: Annelie
authors: A
authors: Blumrich
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
authors: Katharina
authors: K
authors: Focke
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
authors: Sabine
authors: S
authors: Becker
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
authors: Susan
authors: S
authors: Wittig
authors: Institute of Human Genetics, University Hospital of Leipzig, Leipzig, Germany.
authors: Sandra
authors: S
authors: Schinkel
authors: Department of Toxicology, University Medical Center, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
authors: Oliver H
authors: OH
authors: Krämer
authors: Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
authors: James F
authors: JF
authors: Beck
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D002396:Catechols / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D009154:Mutation; D012512:Sarcoma, Ewing / Q000235:genetics / Q000473:pathology*; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C529061:2-(4,5-dihydro-1,3-thiazol-2-ylthio)-1-(3,4-dihydroxyphenyl)ethanone; D000970:Antineoplastic Agents; D002396:Catechols; C495901:TP53 protein, human; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53
keywords: Apoptosis; Cancer therapy; Cell cycle; Ewing’s sarcoma; Gene expression; RETRA; p53; p73