Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells

Maria Serena Benassi, Antonella Chiechi, Francesca Ponticelli, Laura Pazzaglia, Gabriella Gamberi, Licciana Zanella, Maria Cristina Manara, Paola Perego, Stefano Ferrari, Piero Picci

Research output: Contribution to journalArticlepeer-review

Abstract

Since osteosarcoma is a drug-resistant disease, the aim of the present study was to explore the possible interest of therapeutic approaches including nitrogen-containing biphosphonate zoledronic acid using osteosarcoma cell lines with different genetic backgrounds. Parental p53+/pRb+ U2-OS, p53-mutant U2-OS (U2-OS/175) and p53-/pRb- SAOS were sensitive to zoledronic acid with no significant differences in IC50 values. Analysis of cell cycle distribution revealed a time-dependent shifting of U2-OS cells towards G2 phase with cell cycle arrest in G2 phase at 96 h of exposure to the compound. Conversely, U2-OS/175 and SAOS cells responded to treatment with transient cell accumulation in S phase up to 48-72 h, respectively. Cell lines were exposed to increasing concentrations of cisplatin alone or combined with sub-toxic doses of zoledronic acid. A growth inhibitory effect was seen after combined treatment in U2-OS, otherwise resistant to cisplatin up to 100 ng/ml. Zoledronic acid did not efficiently sensitized U2-OS/175 and SAOS to cisplatin, thereby suggesting that different behavior may depend on p53 mutation. This data was confirmed in U2-OS cells where p53 expression was downregulated by RNA interference. Present findings indicate occurrence of sensitization to cisplatin by zoledronic acid in wild-type p53 osteosarcoma cells but not in p53-null cells nor in cells expressing a dominant-negative form of p53, supporting that wild-type p53 is required for synergistic interaction of cisplatin and zoledronic acid.

Original languageEnglish
Pages (from-to)194-205
Number of pages12
JournalCancer Letters
Volume250
Issue number2
DOIs
Publication statusPublished - Jun 8 2007

Keywords

  • Cell cycle
  • Cell viability
  • Cisplatin
  • Osteosarcoma cells
  • Zoledronic acid

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology
  • Oncology

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