title: Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to other p53 activating agents.
abstract: Adaptation of wild-type p53 expressing UKF-NB-3 cancer cells to the murine double minute 2 inhibitor nutlin-3 causes de novo p53 mutations at high frequency (13/20) and multi-drug resistance. Here, we show that the same cells respond very differently when adapted to RITA, a drug that, like nutlin-3, also disrupts the p53/Mdm2 interaction. All of the 11 UKF-NB-3 sub-lines adapted to RITA that we established retained functional wild-type p53 although RITA induced a substantial p53 response. Moreover, all RITA-adapted cell lines remained sensitive to nutlin-3, whereas only five out of 10 nutlin-3-adapted cell lines retained their sensitivity to RITA. In addition, repeated adaptation of the RITA-adapted sub-line UKF-NB-3(r)RITA(10 μM) to nutlin-3 resulted in p53 mutations. The RITA-adapted UKF-NB-3 sub-lines displayed no or less pronounced resistance to vincristine, cisplatin, and irradiation than nutlin-3-adapted UKF-NB-3 sub-lines. Furthermore, adaptation to RITA was associated with fewer changes at the expression level of antiapoptotic factors than observed with adaptation to nutlin-3. Transcriptomic analyses indicated the RITA-adapted sub-lines to be more similar at the gene expression level to the parental UKF-NB-3 cells than nutlin-3-adapted UKF-NB-3 sub-lines, which correlates with the observed chemotherapy and irradiation sensitivity phenotypes. In conclusion, RITA-adapted cells retain functional p53, remain sensitive to nutlin-3, and display a less pronounced resistance phenotype than nutlin-3-adapted cells.
authors.affiliation: Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Michaelis
authors.forename: F
authors.initials: F
authors.lastname: Rothweiler
authors.forename: B
authors.initials: B
authors.lastname: Agha
authors.forename: S
authors.initials: S
authors.lastname: Barth
authors.forename: Y
authors.initials: Y
authors.lastname: Voges
authors.forename: N
authors.initials: N
authors.lastname: Löschmann
authors.forename: A
authors.initials: A
authors.lastname: von Deimling
authors.forename: R
authors.initials: R
authors.lastname: Breitling
authors.forename: H Wilhelm
authors.initials: HW
authors.lastname: Doerr
authors.forename: F
authors.initials: F
authors.lastname: Rödel
authors.forename: D
authors.initials: D
authors.lastname: Speidel
authors.forename: J
authors.initials: J
authors.lastname: Cinatl
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014750:Vincristine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D005663:Furans; D007093:Imidazoles; C118989:NSC 652287; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D014750:Vincristine; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin