Inhibition of HIF-1 alpha using a novel Iron facilitator LS5-81 and its anti-cancer activity in hepatocellular carcinoma

2013 Fiscal Year Final Research Report

• Project/Area Number: 23701094
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Clinical oncology
• Research Institution: Asahikawa Medical College
• Principal Investigator: TANAKA Hiroki 旭川医科大学, 医学部, 特任講師 (70596155)
• Project Period (FY): 2011 – 2013
• Keywords: HIF-1alpha / 鉄

Research Abstract

Targeting HIF-1a has been of therapeutic interest. In normoxic conditions, HIF-1a is hydroxylated by prolylhydroxylases (PHDs), which require iron for its activity. The tumor suppressor protein VHL binds to the hydroxylated HIF-1a, which is then degraded by proteasomes. We focused on the degradation machinery of HIF-1a mediated by PHDs. In this study, we aimed to inhibit the expression of HIF-1a protein and growth of hepatocellular carcinoma (HCC) using the iron-facilitating activity of LS5-81. In the human HCC cell lines, a combination of LS5-81 and iron inhibited HIF-1a protein expression. A mutated HIF-1a protein, which has proline residues that were replaced with alanine and transfected into HEK293 cells, was not affected by the combination of LS5-81 and iron. Furthermore, LS5-81 inhibited tumor growth of mouse HCC models. These results indicate that LS5-81 inhibits HIF-1a expression through prolyl-hydroxylation of HIF-1a and might have a therapeutic effect in the treatment of HCC.

Research Products

• [Journal Article] facilitator LS081 reduces hypoxia-inducible factor-1α protein and functions as anticancer agent in hepatocellular carcinoma (2012)
  • Author(s): Tanaka H, Li Z, Ikuta K, Addo L, Akutsu H, Nakamura M, Sasaki K, Ohtake T, Fujiya M, Torimoto Y, Glass J, Kohgo Y. Iron
  • Journal Title: Cancer Sci Volume: 103(4) Pages: 767-74
  • DOI: 10.1111/j.1349-7006.2011.02192.x.
• [Journal Article] Anticancer activity of the iron facilitator LS081 (2011)
  • Author(s): Li Z, Tanaka H, Galiano F, Glass J
  • Journal Title: J Exp Clin Cancer Res Volume: 31 Pages: 30-34
  • DOI: 10.1186/1756-9966-30-34
• [Presentation] 新規鉄輸送促進剤LS081によるHIF-1αを標的とした肝癌治療効果 (2011)
  • Author(s): 田中宏樹,生田克哉,山本昌代、安藤勝祥、河本徹、岡村直香、伊藤貴博、中村正雄,阿久津弘明,佐々木勝則,鳥本悦宏,Zhen Li,Jonathan Glass,高後裕
  • Organizer: 第9回日本臨床腫瘍学会学術集会
  • Place of Presentation: 横浜市
  • Year and Date: 20110000
• [Presentation] A novel iron facilitator LS081 inhibits HIF-1 α protein expression and functions as an anticancer agent (2011)
  • Author(s): 田中宏樹,生田克哉,佐々木勝則,細木卓明,鳥本悦宏,中村正雄,阿久津弘明,Zhen Li,Jonathan Glass,高後裕
  • Organizer: 第70回日本癌学会学術集会
  • Place of Presentation: 名古屋市
  • Year and Date: 20110000
• [Presentation] Glass J A novel iron facilitator LS081 inhibits HIF-1α protein expression and functions as an anticancer agent Podium presentation, Fourth Congress of the International BioIron Society (IBIS) (2011)
  • Author(s): Tanaka H, Ikuta K, Hosoki T, Sasaki K, Nakamura M, Akutsu H, Torimoto Y, Kohgo Y, Li Z
  • Organizer: Biennial World Meeting 2011
  • Place of Presentation: Vncouver, BC, Canada
  • Year and Date: 20110000
• [Presentation] Iron uptake facilitator LS5-81 のHIF-1α発現抑制効果 (2010)
  • Author(s): 田中宏樹,生田克哉,佐々木勝則,細木卓明,鳥本悦宏,中村正雄,阿久津弘明,Zhen Li,Jonathan Glass,高後裕
  • Organizer: 第34回日本鉄バイオサイエンス学会学術集会
  • Place of Presentation: 東京都
  • Year and Date: 20100000