Enhancement mechanisms of cell growth suppression by bisphosphonates in cancer microenvironment

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08423
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: NISHIGUCHI KOHSHI 京都薬科大学, 薬学部, 教授 (80379437)
• Co-Investigator(Kenkyū-buntansha): 辻本 雅之 京都薬科大学, 薬学部, 講師 (90372739) ; 峯垣 哲也 京都薬科大学, 薬学部, 助教 (10549306)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 食道がん / がん微小環境 / 低酸素 / ビスホスホネート

Outline of Final Research Achievements

Tumour hypoxia is a major obstacle in cancer therapy that leads to poor prognosis. Therefore, the development of cancer treatments that are effective
in hypoxia is necessary. Bisphosphonates (BPs), which are used to treat bone disease, are cytotoxic to several cancer cells in normoxia.
In hypoxia, cell growth inhibition by BPs and via zoledronate-induced apoptosis was higher in hypoxia than that in normoxia. Furthermore, geranylgeraniol completely inhibited the growth inhibitory effects of zoledronate. Additionally, the mRNA and protein levels of HMG-CoA reductase significantly decreased in hypoxia. Moreover, simvastatin potentiated the growth inhibitory effect of zoledronate.The cytotoxicity of BPs is potentiated in hypoxia, through the loss of HMG-CoA reductase function. BPs may be effective against cancer in normoxia and hypoxia.

Free Research Field

臨床薬学、臨床薬剤学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、既存の化学療法に全く奏功しない、あるいは高い治療効果を望めない食道がん患者に対して、代替えとなる治療法あるいは治療薬の選択肢を広げるとともに、食道がんに対する新規治療標的を見出し得るという点で極めて重要な基礎的知見である。また、食道がんの治療成績向上のみならず、治療薬候補に乏しい食道がんの新規治療薬の開発に対して有益な情報を付与することから社会的意義は非常に大きいものと考えられる。