title: In vivo selective imaging and inhibition of leukemia stem-like cells using the fluorescent carbocyanine derivative, DiOC5(3).
abstract: Elimination of leukemia stem cells (LSCs) is necessary for the destruction of malignant cell populations. Owing to the very small number of LSCs in leukemia cells, xenotransplantation studies are difficult in terms of functionally and pathophysiologically replicating clinical conditions of cell culture experiments. There is currently a limited number of lead compounds that target LSCs. Using the LSC-xenograft zebrafish screening method we previously developed, we found that the fluorescent compound 3,3'-dipentyloxacarbocyanine iodide (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.
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Systems Pharmacology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Mie University Medical Zebrafish Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Bioinformatics, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Omics Medicine, Mie University Industrial Technology Innovation, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroyanagi
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Ariyoshi
authors.affiliation: Corporate R&D Headquarters, Canon Inc, Ohta-ku, Tokyo 146-8501, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nomoto
authors.affiliation: Corporate R&D Headquarters, Canon Inc, Ohta-ku, Tokyo 146-8501, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Shintou
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Systems Pharmacology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Umemoto
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Systems Pharmacology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Mie University Medical Zebrafish Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Bioinformatics, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Omics Medicine, Mie University Industrial Technology Innovation, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Corporate R&D Headquarters, Canon Inc, Ohta-ku, Tokyo 146-8501, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Systems Pharmacology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Mie University Medical Zebrafish Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Bioinformatics, Mie University Life Science Research Center, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Omics Medicine, Mie University Industrial Technology Innovation, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. Electronic address: tanaka@doc.medic.mie-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002232:Carbocyanines / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005456:Fluorescent Dyes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015027:Zebrafish
chemical_list: D002232:Carbocyanines; D005456:Fluorescent Dyes; D017382:Reactive Oxygen Species; C018528:3,3'-dipentyl-2,2'-oxacarbocyanine
keywords: High-throughput screening; Leukemia stem cell; Xenotransplant; Zebrafish