Targeting cyclooxygenase by indomethacin decelerates progression of acute lymphoblastic leukemia in a xenograft model.
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Date
2019-11-12ICR Author
Author
Richartz, N
Duthil, E
Ford, A
Naderi, EH
Bhagwat, S
Gilljam, KM
Burman, MM
Ruud, E
Blomhoff, HK
Skah, S
Type
Journal Article
Metadata
Show full item recordAbstract
Acute lymphoblastic leukemia (ALL) develops in the bone marrow in the vicinity of stromal cells known to promote tumor development and treatment resistance. We previously showed that the cyclooxygenase (COX) inhibitor indomethacin prevents the ability of stromal cells to diminish p53-mediated killing of cocultured ALL cells in vitro, possibly by blocking the production of prostaglandin E2 (PGE2). Here, we propose that PGE2 released by bone marrow stromal cells might be a target for improved treatment of pediatric ALL. We used a xenograft model of human primary ALL cells in nonobese diabetic-scid IL2rγnull mice to show that indomethacin delivered in the drinking water delayed the progression of ALL in vivo. The progression was monitored by noninvasive in vivo imaging of the engrafted leukemic cells, as well as by analyses of CD19+CD10+ leukemic blasts present in spleen or bone marrow at the termination of the experiments. The indomethacin treatment increased the level of p53 in the leukemic cells, implying that COX inhibition might reduce progression of ALL by attenuating protective paracrine PGE2 signaling from bone marrow stroma to leukemic cells.
Collections
Subject
Cell Line, Tumor
Tumor Cells, Cultured
Bone Marrow
Animals
Humans
Mice
Disease Models, Animal
Disease Progression
Indomethacin
Dinoprostone
Cyclooxygenase Inhibitors
Xenograft Model Antitumor Assays
Immunophenotyping
Child
Child, Preschool
Male
Prostaglandin-Endoperoxide Synthases
Tumor Suppressor Protein p53
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Biomarkers
Research team
Biology of Childhood Leukaemia
Language
eng
Date accepted
2019-09-05
License start date
2019-11
Citation
Blood advances, 2019, 3 (21), pp. 3181 - 3190
Publisher
AMER SOC HEMATOLOGY