Zoledronic acid significantly enhances radiation‑induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Koto,Kazutaka; Murata,Hiroaki; Kimura,Shinya; Sawai,Yasushi; Horie,Naoyuki; Matsui,Takaaki; Ryu,Kazuteru; Ashihara,Eishi; Maekawa,Taira; Kubo,Toshikazu; Fushiki,Shinji

doi:10.3892/ijo.2012.1735

Zoledronic acid significantly enhances radiation‑induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling

Authors:
- Kazutaka Koto
- Hiroaki Murata
- Shinya Kimura
- Yasushi Sawai
- Naoyuki Horie
- Takaaki Matsui
- Kazuteru Ryu
- Eishi Ashihara
- Taira Maekawa
- Toshikazu Kubo
- Shinji Fushiki
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Affiliations: Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan, Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan, Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan, Department of Pathology and Applied Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan
Published online on: December 12, 2012 https://doi.org/10.3892/ijo.2012.1735
Pages: 525-534

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Abstract

Zoledronic acid (ZOL), a third-generation bisphosphonate, inhibits bone resorption, as well as exhibiting direct antitumor activity. To date, however, the combined effects of ZOL and ionizing radiation (IR) have not been assessed in patients with soft tissue sarcoma. We have, therefore, assessed the combined effects of ZOL and IR in fibrosarcoma cells. HT1080 fibrosarcoma cells were treated with ZOL and/or IR, together or sequentially and the antitumor effects were assessed. We found that ZOL significantly enhanced IR-induced apoptosis, especially when cells were treated with ZOL followed by IR. We, therefore, assessed the detailed mechanism of sequential treatment with ZOL and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of ZOL. However, the levels of expression of Akt, ERK1/2 and NF-κB proteins, all of which are related to radioadaptive resistance, were increased within a short time after irradiation with 3 Gy, and this expression was inhibited by a low concentration of ZOL, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS). These results suggest that the combination of ZOL with IR may be beneficial in treating patients with soft tissue sarcoma.

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