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

• Published in: Cancer letters 2007-06, Vol.250 (2), p.194-205
• Main Authors: Benassi, Maria Serena, Chiechi, Antonella, Ponticelli, Francesca, Pazzaglia, Laura, Gamberi, Gabriella, Zanella, Licciana, Manara, Maria Cristina, Perego, Paola, Ferrari, Stefano, Picci, Piero
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Blotting, Western; Cell culture; Cell cycle; Cell Cycle - drug effects; Cell Division - drug effects; Cell growth; Cell Line, Tumor; Cell viability; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Clinical trials; Diphosphonates - pharmacology; Drug dosages; Drug resistance; Drug Screening Assays, Antitumor; Hematology, Oncology and Palliative Medicine; Humans; Imidazoles - pharmacology; Medical prognosis; Osteosarcoma - metabolism; Osteosarcoma - pathology; Osteosarcoma cells; Retinoblastoma Protein - metabolism; RNA, Small Interfering; Studies; Tumor Suppressor Protein p53 - metabolism; Tumors; Zoledronic acid
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2006.10.004

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.