in vivo Mechanisms of Novel Selective Fluorescent Leukemia Stem Cell Inhibitor

2015 Fiscal Year Final Research Report

• Project/Area Number: 15K15051
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Mie University
• Principal Investigator: Tanaka Toshio 三重大学, 医学(系)研究科(研究院), 教授 (00135443)
• Co-Investigator(Kenkyū-buntansha): Nishimura Yuhei 三重大学, 大学院医学系研究科, 准教授 (30303720) ; Kawase Reiko 三重大学, 大学院医学系研究科, 助教 (50746740)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Keywords: ヒトがん幹細胞阻害薬 / ZM-B708 / 悪性腫瘍治療抵抗性 / ヒトがん幹細胞治療薬 / ゼブラフィッシュ / 免疫不全マウス / 蛍光試薬 / がん幹細胞選択性

Outline of Final Research Achievements

Elimination of leukemia stem cells is necessary for the destruction of malignant cell populations. Using the LSC-xenograft zebrafish screening method we previously developed, we found that the fluorescent compound DiOC5(3) selectively marked LSCs and suppressed their proliferation in vivo and in vitro. DiOC5(3) had no obvious toxicity to human umbilical cord blood CD34+ progenitor cells and normal zebrafish. It accumulated in mitochondria through organic anion transporter polypeptides that are overexpressed in the plasma membrane of LSCs, and induced apoptosis via ROS overproduction. DiOC5(3) also inhibited the nuclear translocation of NF-κB through the downregulation of LSC-selective pathways, as indicated from DNA microarray analysis. In summary, DiOC5(3) is a new type of anti-LSC compound available for diagnostic imaging and therapeutics that has the advantage of being a single fluorescent chemical.

Free Research Field

システムズ薬理学