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Biomaterials. 2015 Jun;52:14-25. doi: 10.1016/j.biomaterials.2015.02.009. Epub 2015 Feb 21.

In vivo selective imaging and inhibition of leukemia stem-like cells using the fluorescent carbocyanine derivative, DiOC5(3).

Author information

1
Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
2
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.
3
Corporate R&D Headquarters, Canon Inc, Ohta-ku, Tokyo 146-8501, Japan.
4
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.
5
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.

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.

KEYWORDS:

High-throughput screening; Leukemia stem cell; Xenotransplant; Zebrafish

[Indexed for MEDLINE]

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