RRC ID 44869
Author Zhang B, Shimada Y, Kuroyanagi J, Umemoto N, Nishimura Y, Tanaka T.
Title Quantitative phenotyping-based in vivo chemical screening in a zebrafish model of leukemia stem cell xenotransplantation.
Journal PLoS ONE
Abstract Zebrafish-based chemical screening has recently emerged as a rapid and efficient method to identify important compounds that modulate specific biological processes and to test the therapeutic efficacy in disease models, including cancer. In leukemia, the ablation of leukemia stem cells (LSCs) is necessary to permanently eradicate the leukemia cell population. However, because of the very small number of LSCs in leukemia cell populations, their use in xenotransplantation studies (in vivo) and the difficulties in functionally and pathophysiologically replicating clinical conditions in cell culture experiments (in vitro), the progress of drug discovery for LSC inhibitors has been painfully slow. In this study, we developed a novel phenotype-based in vivo screening method using LSCs xenotransplanted into zebrafish. Aldehyde dehydrogenase-positive (ALDH+) cells were purified from chronic myelogenous leukemia K562 cells tagged with a fluorescent protein (Kusabira-orange) and then implanted in young zebrafish at 48 hours post-fertilization. Twenty-four hours after transplantation, the animals were treated with one of eight different therapeutic agents (imatinib, dasatinib, parthenolide, TDZD-8, arsenic trioxide, niclosamide, salinomycin, and thioridazine). Cancer cell proliferation, and cell migration were determined by high-content imaging. Of the eight compounds that were tested, all except imatinib and dasatinib selectively inhibited ALDH+ cell proliferation in zebrafish. In addition, these anti-LSC agents suppressed tumor cell migration in LSC-xenotransplants. Our approach offers a simple, rapid, and reliable in vivo screening system that facilitates the phenotype-driven discovery of drugs effective in suppressing LSCs.
Volume 9(1)
Pages e85439
Published 2014
DOI 10.1371/journal.pone.0085439
PII PONE-D-13-29601
PMID 24454867
PMC PMC3893211
MeSH Aldehyde Dehydrogenase / metabolism Animals Antineoplastic Agents / pharmacology Base Sequence DNA Primers Humans K562 Cells Leukemia, Myelogenous, Chronic, BCR-ABL Positive / therapy* Neoplastic Stem Cells / drug effects Neoplastic Stem Cells / transplantation* Phenotype Polymerase Chain Reaction Stem Cell Transplantation* Transplantation, Heterologous Zebrafish
IF 2.766
Times Cited 17
Human and Animal Cells