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Abstract
Osteosarcoma (OSA) is the most common malignant bone tumor in children and adolescents. The overall five-year survival rate for all bone cancers is below 70%; however, when the cancer has spread beyond the bone, it is about 15-30%. Herein, we evaluated the effects of carbon-ion beam irradiation alone or in combination with zoledronic acid (ZOL) on OSA cells. Carbon-ion beam irradiation in combination with ZOL significantly inhibited OSA cell proliferation by arresting cell cycle progression and initiating KHOS and U2OS cell apoptosis, compared to treatments with carbon-ion beam irradiation, X-ray irradiation, and ZOL alone. Moreover, we observed that this combination greatly inhibited OSA cell motility and invasion, accompanied by the suppression of the Pi3K/Akt and MAPK signaling pathways, which are related to cell proliferation and survival, compared to individual treatments with carbon-ion beam or X-ray irradiation, or ZOL. Furthermore, ZOL treatment upregulated microRNA (miR)-29b expression; the combination with a miR-29b mimic further decreased OSA cell viability via activation of the caspase 3 pathway. Thus, ZOL-mediated enhancement of carbon-ion beam radiosensitivity may occur via miR-29b upregulation; co-treatment with the miR-29b mimic further decreased OSA cell survival. These findings suggest that the carbon-ion beam irradiation in combination with ZOL has high potential to increase OSA cell death.

Author information

Kim EH1, Kim MS2, Takahashi A3, Suzuki M4, Vares G5, Uzawa A4, Fujimori A4, Ohno T6, Sai S4.
1
Department of Biochemistry, School of Medicine, Daegu Catholic University, Nam-gu, Daegu 42472, Korea.
2
Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
3
Gunma University Heavy Ion Medical Center, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan.
4
Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
5
Cell Signal Unit, Okinawa Institute of Science and Technology Graduate University (OIST), Onna-son 904-0495, Okinawa, Japan.
6
Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan.