Zoledronic acid is an effective radiosensitizer in the treatment of osteosarcoma

// Eun Ho Kim 1 , Mi-Sook Kim 2, * , Kyung-Hee Lee 3 , Jae-Soo Koh 4 , Won-Gyun Jung 1 , Chang-Bae Kong 3, * 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 * These authors have contributed equally to this work Correspondence to: Mi-Sook Kim, email: mskim@kirams.re.kr Chang-Bae Kong, email: cbkongmd@gmail.com Keywords: zoledronic acid, radiosensitivity, osteosarcoma cells, apoptosis, DNA damage Received: December 30, 2015 Accepted: September 12, 2016 Published: September 27, 2016 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 mm 3 following γ-irradiation (8 Gy), while it was 150 mm 3 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.