Investigational New Drugs

, Volume 32, Issue 5, pp 783–794 | Cite as

PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines

  • Patricia Izetti
  • Agnes Hautefeuille
  • Ana Lucia Abujamra
  • Caroline Brunetto de Farias
  • Juliana Giacomazzi
  • Bárbara Alemar
  • Guido Lenz
  • Rafael Roesler
  • Gilberto Schwartsmann
  • Alessandro Bersch Osvaldt
  • Pierre Hainaut
  • Patricia Ashton-Prolla
PRECLINICAL STUDIES

Summary

TP53 mutation is a common event in many cancers, including pancreatic adenocarcinoma, where it occurs in 50–70 % of cases. In an effort to reactivate mutant p53 protein, several new drugs are being developed, including PRIMA-1 and PRIMA-1Met/APR-246 (p53 reactivation and induction of massive apoptosis). PRIMA-1 has been shown to induce apoptosis in tumor cells by reactivating p53 mutants, but its effect in pancreatic cancer remains unclear. Here we investigated the effects of PRIMA-1 on cell viability, cell cycle and expression of p53-regulated proteins in PANC-1 and BxPC-3 (mutant TP53), and CAPAN-2 (wild-type TP53) pancreatic cell lines. Treatment with PRIMA-1 selectively induced apoptosis and cell cycle arrest in p53 mutant cells compared to CAPAN-2 cells. The growth suppressive effect of PRIMA-1 was markedly reduced in p53 mutant cell lines transfected with p53 siRNA, supporting the role of mutant p53 in PRIMA-1 induced cell death. Moreover, treatment with the thiol group donor N-acetylcysteine completely blocked PRIMA-1-induced apoptosis and reinforced the hypothesis that thiol modifications are important for PRIMA-1 biological activity. In combination treatments, PRIMA-1 enhanced the anti-tumor activity of several chemotherapic drugs against pancreatic cancer cells and also exhibited a pronounced synergistic effect in association with the Mdm2 inhibitor Nutlin-3. Taken together, our data indicate that PRIMA-1 induces apoptosis in p53 mutant pancreatic cancer cells by promoting the re-activation of p53 and inducing proapoptotic signaling pathways, providing in vitro evidence for a potential therapeutic approach in pancreatic cancer.

Keywords

Pancreatic cancer p53 PRIMA-1 Apoptosis 

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Patricia Izetti
    • 1
    • 2
    • 3
    • 13
  • Agnes Hautefeuille
    • 4
  • Ana Lucia Abujamra
    • 3
    • 5
    • 6
  • Caroline Brunetto de Farias
    • 3
    • 5
    • 6
  • Juliana Giacomazzi
    • 1
  • Bárbara Alemar
    • 1
    • 2
  • Guido Lenz
    • 7
  • Rafael Roesler
    • 3
    • 6
    • 8
  • Gilberto Schwartsmann
    • 3
    • 6
    • 9
  • Alessandro Bersch Osvaldt
    • 10
  • Pierre Hainaut
    • 11
  • Patricia Ashton-Prolla
    • 1
    • 2
    • 12
  1. 1.Laboratório de Medicina Genômica, Centro de Pesquisa ExperimentalHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  2. 2.Programa de Pós-Graduação em Genética e Biologia MolecularUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  3. 3.Laboratório de Pesquisas em Câncer, Centro de Pesquisa ExperimentalHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  4. 4.International Agency for Research on CancerLyonFrance
  5. 5.Instituto do Câncer Infantil do Rio Grande do SulPorto AlegreBrazil
  6. 6.Instituto Nacional de Ciência e Tecnologia Translacional em MedicinaPorto AlegreBrazil
  7. 7.Laboratório de Sinalização e Plasticidade CelularUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  8. 8.Laboratório de Neurofarmacologia e Biologia de Tumores Neurais, Departamento de Farmacologia, Instituto de Ciências Básicas da SaúdeUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  9. 9.Serviço de Oncologia ClínicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  10. 10.Serviço de Cirurgia do Aparelho DigestivoHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  11. 11.International Prevention Research InstituteLyonFrance
  12. 12.Departamento de GenéticaUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  13. 13.Laboratório de Medicina GenômicaHospital de Clínicas de Porto AlegrePorto AlegreBrazil

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