Development of new treatments against malignant bone and soft tissue tumors by using bisphosphonate and ionizing radiation

2013 Fiscal Year Final Research Report

• Project/Area Number: 23592196
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: MURATA Hiroaki 京都府立医科大学, 医学(系)研究科(研究院), 客員講師 (90360031)
• Co-Investigator(Kenkyū-buntansha): KOTO Kazutaka 明治国際医療大学, 公私立大学の部局等, 講師 (50649340)
• Co-Investigator(Renkei-kenkyūsha): MAEKAWA Taira 京都大学, 大学院医学研究科, 教授 (80229286) ; KIMURA Shinya 佐賀大学, 医学部, 教授 (80359794) ; ASHIHARA Eishi 京都薬科大学, 薬学部, 教授 (70275197)
• Project Period (FY): 2011 – 2013
• Keywords: ビスホスフォネート / 軟部肉腫 / 放射線治療 / アポトーシス / 骨肉腫

Research Abstract

Fibrosarcoma cells were treated with third-generation bisphosphonate (BPs) and/or ionizing radiation (IR), together or sequentially, and the antitumor effects were assessed. BPs significantly enhanced IR-induced apoptosis, especially when cells were treated with BPs followed by IR. We therefore assessed the detailed mechanism of sequential treatment with BPs and IR. Cells in G2 and M phases, the most radiosensitive phases of the cell cycle, were not increased by low concentrations of BPs. However, the levels of expression of Akt, ERK1/2, and NF- B 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 BPs, which blocked the prenylation of small GTPases. This sequential treatment also increased the generation of reactive oxygen species (ROS).

Research Products

• [Journal Article] Zoledronic acid significantly enhances radiation‑induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling (2013)
  • Author(s): Koto K, Murata H, Kimura S, Sawai Y, Horie N, Matsui T, Ryu K, Ashihara E, Maekawa T, Kubo T, Fushiki S
  • Journal Title: Int J Oncol Volume: 42 (Epub 2012 Dec 12) Pages: 525-534
  • DOI: 10.3892/ijo.2012.1735
  • Peer Reviewed
• [Presentation] The third-generation bisphosphonate shows combined effects with anti-tumor drugs in human fibrosarcoma cells (2013)
  • Author(s): Murata H, Koto K, Sawai Y, Matsui TA, Horie N, Fushiki S, Kimura S, Maekawa T, Horii M, Kubo T
  • Organizer: International Society of Limb Salvage 17th General Meeting
  • Place of Presentation: Bologna, Italy
  • Year and Date: 20130911-13
• [Presentation] Zoledronic acid significantly enhances radiation-induced apoptosis against human fibrosarcoma cells by inhibiting radioadaptive signaling (2013)
  • Author(s): Koto K, Murata H, Matsui TA, Horie N, Sawai Y, Ashihara E, Kimura S, Maekawa T, Fushiki S, Horii M, Kubo T
  • Organizer: International Society of Limb Salvage 17th General Meeting
  • Place of Presentation: Bologna, Italy
  • Year and Date: 20130911-13
• [Presentation] 線維肉腫細胞株に対するゾレドロン酸と放射線の併用による細胞内シグナル伝達経路への影響の検討 (2012)
  • Author(s): 小藤和孝,堀井基行,村田博昭,松井隆明,堀江直行,澤井泰志,久保俊一
  • Organizer: 第27回日本整形外科学会基礎学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 20121026-27
• [Presentation] Combined effects of the Third-Generation Bisphosphonate and Radiation on Fibrosarcoma Cells (2012)
  • Author(s): Koto K, Murata H, Sakabe T, Matsui TA, Horie N, Sawai Y, Ashihara E, Kimura S, Maekawa T, Fushiki S, Kubo T
  • Organizer: 13th EFORT Congress
  • Place of Presentation: Berlin, Germany
  • Year and Date: 2012-05-25
• [Presentation] 線維肉細胞株に対する第3世代ビスフォスフォネートと放射線の併用による抗腫瘍効果の検討 (2011)
  • Author(s): 小藤和孝,村田博昭,坂部智哉,松井隆明,堀江直行,澤井泰志,久保俊一
  • Organizer: 第44回日本整形外科学会骨・軟部腫瘍学術集会
  • Place of Presentation: 京都
  • Year and Date: 20110714-15
• [Presentation] 線維肉細胞株に対するゾレドロン酸と放射線の併用によるアポトーシス誘導効果および細胞内シグナル伝達経路への影響の検討 (2011)
  • Author(s): 小藤和孝,村田博昭,坂部智哉,大島康史,松井隆明,堀江直行,澤井泰志,久保俊一
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: 前橋
  • Year and Date: 2011-10-21