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Human neuroblastoma cells with acquired resistance to the p53 activator RITA retain functional p53 and sensitivity to

M Michaelis1, F Rothweiler, B Agha

  • 1Institut für Medizinische Virologie, Klinikum der Goethe-Universität, Paul Ehrlich-Str. 40, 60596 Frankfurt am Main, Germany.

Cell Death & Disease
|April 6, 2012
PubMed

Insights

Adapting cancer cells to RITA preserves functional p53 and sensitivity to nutlin-3, unlike nutlin-3 adaptation which causes p53 mutations and drug resistance. RITA-adapted cells show less resistance to chemotherapy and irradiation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance

Background:

  • The p53 protein is a critical tumor suppressor.
  • Inhibitors of the p53-MDM2 interaction, such as nutlin-3 and RITA, are investigated as cancer therapeutics.
  • Cancer cells can develop resistance to these drugs, often through p53 mutations.

Purpose of the Study:

  • To compare the adaptation of UKF-NB-3 cancer cells to RITA versus nutlin-3.
  • To investigate the impact of RITA adaptation on p53 function, drug sensitivity, and gene expression.
  • To determine if RITA adaptation confers cross-resistance to other therapies.

Main Methods:

  • Adaptation of UKF-NB-3 cells to increasing concentrations of RITA or nutlin-3.
  • Assessment of p53 mutational status.
  • Evaluation of drug sensitivity (nutlin-3, vincristine, cisplatin) and irradiation sensitivity.
  • Analysis of antiapoptotic factor expression.
  • Transcriptomic analysis of adapted cell lines.

Main Results:

  • RITA-adapted cells retained functional wild-type p53, unlike nutlin-3-adapted cells which frequently acquired p53 mutations.
  • RITA-adapted cells remained sensitive to nutlin-3, while nutlin-3-adapted cells showed reduced sensitivity to RITA.
  • RITA-adapted cells exhibited less resistance to vincristine, cisplatin, and irradiation compared to nutlin-3-adapted cells.
  • Transcriptomic profiles of RITA-adapted cells were more similar to parental cells than nutlin-3-adapted cells.

Conclusions:

  • Adaptation to RITA preserves p53 functionality and sensitivity to nutlin-3.
  • RITA adaptation results in a less pronounced multi-drug resistance phenotype compared to nutlin-3 adaptation.
  • RITA represents a potentially advantageous therapeutic strategy due to retained p53 function and reduced resistance development.

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