title: MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: role of p53.
abstract: P53 is rarely mutated in cutaneous T-cell lymphoma (CTCL) and is therefore a promising target for innovative therapeutic approaches. Nutlin-3a is an inhibitor of MDM2 (human homolog of murine double minute 2), which disrupts its interaction with p53, leading to the stabilization and activation of p53. To investigate the potential therapeutic use of nutlin-3a in CTCL, we screened CTCL lines Hut-78, SeAx, MyLa2000, Mac1, and Mac2a by measuring p53 levels after nutlin-3a treatment. In MyLa2000, Mac1, and Mac2a, we observed the increase in p53, indicating the fully functional p53. In the remaining cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block and expression of the senescence-associated β-galactosidase. This effect was abolished in cells in which p53 was silenced by small interfering RNA. Sézary cells lack functional p53 and were resistant to nutlin-3a. However, nutlin-3a potentiated the efficacy of conventional chemotherapeutics not only in cells with intact p53 but also in Hut-78, SeAx, and Sézary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells.
authors.affiliation: Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark. valentinamanfe@libero.it
authors.forename: Valentina
authors.initials: V
authors.lastname: Manfé
authors.forename: Edyta
authors.initials: E
authors.lastname: Biskup
authors.forename: Peter
authors.initials: P
authors.lastname: Johansen
authors.forename: Maria R
authors.initials: MR
authors.lastname: Kamstrup
authors.forename: Thorbjørn F
authors.initials: TF
authors.lastname: Krejsgaard
authors.forename: Niels
authors.initials: N
authors.lastname: Morling
authors.forename: Hans C
authors.initials: HC
authors.lastname: Wulf
authors.forename: Robert
authors.initials: R
authors.lastname: Gniadecki
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D018389:Codon, Nonsense; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors; D034741:RNA, Small Interfering / Q000494:pharmacology; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018389:Codon, Nonsense; D007093:Imidazoles; D010879:Piperazines; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D051736:Proto-Oncogene Proteins c-mdm2