Oncotarget

Research Papers:

Zoledronic acid is an effective radiosensitizer in the treatment of osteosarcoma

Eun Ho Kim, Mi-Sook Kim _, Kyung-Hee Lee, Jae-Soo Koh, Won-Gyun Jung and Chang-Bae Kong

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Oncotarget. 2016; 7:70869-70880. https://doi.org/10.18632/oncotarget.12281

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Abstract

Eun Ho Kim1, Mi-Sook Kim2,*, Kyung-Hee Lee3, Jae-Soo Koh4, Won-Gyun Jung1, Chang-Bae Kong3,*

1Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea

2Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea

3Department of Orthopaedic Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, South Korea

4Department 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 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.


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