title: Zoledronic acid significantly enhances radiation‑induced apoptosis against             human fibrosarcoma cells by inhibiting radioadaptive signaling.
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.
authors.affiliation: Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Koto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Murata
authors.forename: Shinya
authors.initials: S
authors.lastname: Kimura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sawai
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Horie
authors.forename: Takaaki
authors.initials: T
authors.lastname: Matsui
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Ryu
authors.forename: Eishi
authors.initials: E
authors.lastname: Ashihara
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Kubo
authors.forename: Shinji
authors.initials: S
authors.lastname: Fushiki
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects* / Q000528:radiation effects; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011839:Radiation, Ionizing; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D017382:Reactive Oxygen Species; D000077211:Zoledronic Acid