title: PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53.
abstract: OBJECTIVE
  Small cell lung cancer (SCLC) is a highly malignant disease with poor prognosis, necessitating the need to develop new and efficient treatment modalities. PRIMA-1(Met) (p53-dependent reactivation of massive apoptosis), also known as APR-246, is a small molecule, which restores tumor suppressor function to mutant p53 and induces cancer cell death in various cancer types. Since p53 is mutated in more than 90% of SCLC, we investigated the ability of PRIMA-1(Met) to induce apoptosis and inhibit tumor growth in SCLC with different p53 mutations.
  
  
  METHODS
  The therapeutic effect of PRIMA-1(Met)/APR-246 was studied in SCLC cells in vitro using cell viability assay, fluorescence-activated cell-sorting analysis, p53 knockdown studies, and Western blot analyses. The antitumor potential of PRIMA-1(Met)/APR-246 was further evaluated in two different SCLC xenograft models.
  
  
  RESULTS
  PRIMA-1(Met)/APR-246 efficiently inhibited the growth of the SCLC cell lines expressing mutant p53 in vitro and induced apoptosis, associated with increased fraction of cells with fragmented DNA, caspase-3 activation, PARP cleavage, Bax and Noxa upregulation and Bcl-2 downregulation in the cells. The growth suppressive effect of PRIMA-1(Met)/APR-246 was markedly reduced in SCLC cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1(Met)/APR-246-induced cell death. Moreover, in vivo studies showed significant antitumor effects of PRIMA-1(Met) after i.v. injection in SCLC mouse models with no apparent toxicity.
  
  
  CONCLUSIONS
  This study is the first to show the potential use of p53-reactivating molecules such as PRIMA-1(Met)/APR-246 for the treatment of SCLC.
authors.affiliation: Department of Radiation Biology, The Finsen Centre, Copenhagen University Hospital, Copenhagen, Denmark. roza@rh.dk
authors.forename: Roza
authors.initials: R
authors.lastname: Zandi
authors.forename: Galina
authors.initials: G
authors.lastname: Selivanova
authors.forename: Camilla Laulund
authors.initials: CL
authors.lastname: Christensen
authors.forename: Thomas Alexander
authors.initials: TA
authors.lastname: Gerds
authors.forename: Berthe Marie
authors.initials: BM
authors.lastname: Willumsen
authors.forename: Hans Skovgaard
authors.initials: HS
authors.lastname: Poulsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018450:Disease Progression; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011812:Quinuclidines / Q000494:pharmacology* / Q000627:therapeutic use*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D050505:Mutant Proteins; D011812:Quinuclidines; C533410:eprenetapopt