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Growth inhibition and sensitization to cisplatin by zoledronic acid in osteosarcoma cells
Maria Serena Benassi1, Antonella Chiechi, Francesca Ponticelli
1Laboratory of Oncologic Research, Rizzoli Orthopaedic Institute, Bologna, Italy. mariaserena.benassi@ior.it
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.
Insights
Zoledronic acid sensitizes osteosarcoma cells with wild-type p53 to cisplatin, enhancing drug efficacy. This synergistic effect, however, is not observed in osteosarcoma cells with mutated or absent p53.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Osteosarcoma exhibits significant drug resistance, necessitating novel therapeutic strategies.
- Zoledronic acid, a nitrogen-containing bisphosphonate, is being investigated for its potential in cancer treatment.
- The role of p53 tumor suppressor protein in drug response is critical in various cancers.
Purpose of the Study:
- To investigate the efficacy of zoledronic acid in combination with cisplatin against osteosarcoma cell lines.
- To determine the influence of p53 genetic status on the response to zoledronic acid and cisplatin treatment.
- To explore the potential of zoledronic acid as a chemosensitizer in drug-resistant osteosarcoma.
Main Methods:
- Utilized osteosarcoma cell lines with varying p53 and pRb statuses (U2-OS, U2-OS/175, SAOS).
- Assessed sensitivity to zoledronic acid and cisplatin through IC50 value determination and cell cycle analysis.
- Investigated the synergistic effect of combined zoledronic acid and cisplatin treatment, including p53 knockdown experiments using RNA interference.
Main Results:
- Zoledronic acid demonstrated sensitivity across different osteosarcoma cell lines, inducing G2 cell cycle arrest in wild-type p53 cells.
- Combined treatment of zoledronic acid and cisplatin showed significant growth inhibition in wild-type p53 U2-OS cells, which were otherwise cisplatin-resistant.
- Zoledronic acid failed to sensitize p53-mutant (U2-OS/175) and p53-null (SAOS) osteosarcoma cells to cisplatin.
Conclusions:
- Wild-type p53 is essential for the synergistic interaction between zoledronic acid and cisplatin in osteosarcoma.
- Zoledronic acid can act as a chemosensitizer for cisplatin in osteosarcoma cells expressing wild-type p53.
- The p53 mutational status significantly impacts the therapeutic response to combined zoledronic acid and cisplatin treatment in osteosarcoma.
