title: Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells.
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.
authors.affiliation: Laboratory of Oncologic Research, Rizzoli Orthopaedic Institute, Bologna, Italy. mariaserena.benassi@ior.it
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Benassi
authors.forename: Antonella
authors.initials: A
authors.lastname: Chiechi
authors.forename: Francesca
authors.initials: F
authors.lastname: Ponticelli
authors.forename: Laura
authors.initials: L
authors.lastname: Pazzaglia
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gamberi
authors.forename: Licciana
authors.initials: L
authors.lastname: Zanella
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Manara
authors.forename: Paola
authors.initials: P
authors.lastname: Perego
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D007093:Imidazoles; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D000077211:Zoledronic Acid; D002945:Cisplatin