title: Zoledronic acid is an effective radiosensitizer in the treatment of osteosarcoma.
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.
authors.affiliation: Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Eun Ho
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Mi-Sook
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Orthopaedic Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Jae-Soo
authors.initials: JS
authors.lastname: Koh
authors.affiliation: Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Won-Gyun
authors.initials: WG
authors.lastname: Jung
authors.affiliation: Department of Orthopaedic Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea.
authors.forename: Chang-Bae
authors.initials: CB
authors.lastname: Kong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001859:Bone Neoplasms / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy / Q000379:methods; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D004164:Diphosphonates / Q000627:therapeutic use*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007150:Immunohistochemistry; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012516:Osteosarcoma / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011829:Radiation Dosage; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; D000077211:Zoledronic Acid
keywords: DNA damage; apoptosis; osteosarcoma cells; radiosensitivity; zoledronic acid