15-hydroxyprostaglandin dehydrogenase (15-PGDH), that acts in vivo as a negative regulator of prostaglandin levels and activity, catalyzes the first step in the degradation of prostanoid family molecules, oxidizing the prostanoid 15-hydroxyl group to a ketone, and thereby abrogating binding to prostaglandin receptors. SW033291 is a potent inhibitor of 15-PGDH enzyme activity with IC50 and Kiapp of 1.5 nM and 0.1 nM, respectively. In Vaco-503 cells, SW033291 (2.5 μM) decreased cellular 15-PGDH enzyme activity by 85%. Treatment of A549 cells with SW033291 increased PGE2 levels by 3.5-fold at 500 nM, with 50% of maximal stimulation (EC50) at approximately 75 nM. Importantly, mice injected with SW033291 closely phenocopied 15-PGDH knockout mice, with 10 mg/kg SW033291 inducing a 2-fold increase in PGE2 levels in bone marrow, colon, lung and liver. Mice injected with SW033291 for three consecutive days showed similar significant benefits, including a doubling of peripheral neutrophil counts, a 65% increase in marrow SKL cells, and a 71% increase in marrow SLAM cells. In functional assays, bone marrow from SW033291-treated (10 mg/kg IP twice daily for 5 doses) mice showed significant 55% increases in the numbers of hematopoietic colonies generated after plating into methylcellulose. Likewise, ex vivo treatment of harvested bone marrow cells with SW033291 induced a significant 50% increase in hematopoietic colony formation[2].
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