Targeting cyclooxygenase by indomethacin decelerates progression of acute lymphoblastic leukemia in a xenograft model.
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Embargo End Date
ICR Authors
Authors
Richartz, N
Duthil, E
Ford, A
Naderi, EH
Bhagwat, S
Gilljam, KM
Burman, MM
Ruud, E
Blomhoff, HK
Skah, S
Duthil, E
Ford, A
Naderi, EH
Bhagwat, S
Gilljam, KM
Burman, MM
Ruud, E
Blomhoff, HK
Skah, S
Document Type
Journal Article
Date
2019-11-12
Date Accepted
2019-09-05
Abstract
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 IL2rĪ³null 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.
Citation
Blood advances, 2019, 3 (21), pp. 3181 - 3190
Source Title
Publisher
AMER SOC HEMATOLOGY
ISSN
2473-9529
eISSN
2473-9537
Collections
Research Team
Biology of Childhood Leukaemia