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Oncotarget. 2016 Oct 25;7(43):70869-70880. doi: 10.18632/oncotarget.12281.

Zoledronic acid is an effective radiosensitizer in the treatment of osteosarcoma.

Author information

1
Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
2
Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
3
Department of Orthopaedic Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
4
Department of Pathology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.

Abstract

To overcome radioresistance in the treatment of osteosarcoma, a primary malignant tumor of the bone, radiotherapy is generally combined with radiosensitizers. The purpose of this study was to investigate a third-generation bisphosphonate, zoledronic acid (ZOL), as a radiosensitizer for osteosarcoma. We found that exposure of KHOS/NP osteosarcoma cells to 20 μM ZOL decreased the γ-radiation dose needed to kill 90% of cells. This radiosensitizing effect of ZOL was mediated through decreased mitochondrial membrane potential, increased levels of reactive oxygen species, increased DNA damage (as assessed by counting γ-H2AX foci), decreased abundance of proteins involved in DNA repair pathways (ATR, Rad52, and DNA-PKcs), and decreased phosphorylation of PI3K-Akt and MAPK pathway proteins (Raf1, MEK1/2, ERK1/2, and Akt), as compared to γ-irradiation alone. Cells treated with ZOL plus γ-irradiation showed impaired cell migration and invasion and reduced expression of epithelial-mesenchymal transition markers (vimentin, MMP9, and Slug). In Balb/c nude mice, the mean size of orthotopic osteosarcoma tumors 2 weeks post-inoculation was 195 mm3 following γ-irradiation (8 Gy), while it was 150 mm3 after γ-irradiation plus ZOL treatment (0.1 mg/kg twice weekly for 2 weeks). These results provide a rationale for combining ZOL with radiotherapy to treat osteosarcoma.

KEYWORDS:

DNA damage; apoptosis; osteosarcoma cells; radiosensitivity; zoledronic acid

PMID:
27765919
PMCID:
PMC5342595
DOI:
10.18632/oncotarget.12281
[Indexed for MEDLINE]
Free PMC Article

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