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: Beibei Zhang, Yasuhito Shimada, Junya Kuroyanagi, Michiko Ariyoshi, Tsuyoshi Nomoto, Taichi Shintou, Noriko Umemoto, Yuhei Nishimura, Takeshi Miyazaki, Toshio Tanaka
• Journal: Biomaterials (Biomaterials) Vol. 52 Pg. 14-25 (Jun 2015) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 25818410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Carbocyanines
• Fluorescent Dyes
• Reactive Oxygen Species
• 3,3'-dipentyl-2,2'-oxacarbocyanine

Topics

• Animals
• Apoptosis (drug effects)
• Carbocyanines (pharmacokinetics, pharmacology, therapeutic use)
• Cell Line
• Cell Proliferation (drug effects)
• Fluorescent Dyes (pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Leukemia, Myeloid, Acute (diagnosis, drug therapy, metabolism, pathology)
• Mitochondria (drug effects, metabolism, pathology)
• Neoplastic Stem Cells (drug effects, pathology)
• Reactive Oxygen Species (metabolism)
• Zebrafish