Nonsteroidal anti-inflammatory drugs (NSAIDs) or EP4 receptor antagonism enhances hematopoietic stem and progenitor cell (HSPC) mobilization and facilitates faster hematopoietic recovery after myeloablation.

Abstract

6604 Background: We recently reported that Prostaglandin E2 (PGE2) increases homing and engraftment of HSPC to bone marrow (Hoggatt et al, Blood 2009). We hypothesized that blocking PGE2 synthesis via inhibition of cyclooxygenases (COX) by NSAIDs would facilitate HSPC mobilization and serve as an adjunct to current mobilization regimens. Methods: Mice were treated with filgrastim (Neupogen) (FG) with or without co-administration of NSAID or specific agonists and antagonists of PGE2 receptors (EP1-4). HSPC mobilized to peripheral blood were quantitated by colony forming units-granulocyte/macrophage (CFU-GM), by flow cytometry, or in competitive transplantation assays. In addtion, to confirm in a non-human primate model, 4 baboons were mobilized with FG ± NSAID in a crossover protocol. Results: Treatment of mice with NSAID + FG resulted in an increase in CFU-GM over FG alone (1.96 ± 0.19 fold, p < 0.001). NSAID synergistically enhanced mobilization by plerixafor (Mozobil) alone or with GROβ, indicating FG-independent mechanisms. In baboons, NSAID increased CFU-GM (2,845 vs. 5,975, p = 0.03) and CD34+ cells (9,051 vs. 2,6910, p = 0.03) per ml blood. Lethally irradiated mice transplanted with FG + NSAID mobilized grafts exhibited faster recovery of both neutrophils and platelets, with an increase in competitive repopulating units, indicating long-term repopulating cells were mobilized. EP4 antagonists significantly enhanced mobilization (2.02 ± 0.21 fold, p < 0.005), while an EP1-3 antagonist had no effect. Similarly, an EP4 agonist abrogated NSAID enhancement, while EP1-3 agonists did not, indicating that a lack of EP4 receptor signaling is responsible for enhanced HSPC mobilization. Conclusions: Our results define a novel role for NSAIDs and suggest that addition of NSAIDs, particularly Meloxicam, to current mobilization regimens may increase HSPC yield. In addition, we have identified novel mechanisms mediated by EP receptors and show that mobilization can be enhanced through antagonism of the EP4 receptor, defining a new pharmaceutical target for hematopoietic mobilization and transplantation. No significant financial relationships to disclose.