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].
SW033291 细胞实验
Cell Line
Concentration
Treated Time
Description
References
A549 cells
40 nM
Measure PGE2 secretion levels
Haematologica. 2018 Jun;103(6):1054-1064.
A549 cells
20 nM
8 hours
To evaluate the effect of SW033291 on PGE2 levels, results showed that at 20 nM concentration, PGE2 levels increased from 660 pg/mL to 1440 pg/mL, a 2.2-fold increase.
J Med Chem. 2017 May 11;60(9):3979-4001.
A549 cells
500 nM
To evaluate the effect of SW033291 on PGE2 levels, results showed a 3.5-fold increase in PGE2 levels
Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science.
SW033291 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Bone marrow transplantation, ulcerative colitis, and partial hepatectomy models
Intraperitoneal injection
10 mg/kg
Single dose
To evaluate the effect of SW033291 on PGE2 levels in vivo, results showed that PGE2 levels doubled in bone marrow, colon, lung, and liver at 3 hours post-dose.
J Med Chem. 2017 May 11;60(9):3979-4001.
Mice
WT and EP4Avil–/– mice
Injection
10 mg/kg/d
Daily for 1 month
SW033291 significantly increased the number of osteoblasts and decreased the number of adipocytes in WT mice, and these effects were absent in EP4Avil–/– mice.
J Clin Invest. 2020 Jul 1;130(7):3483-3498
Mice
Bone marrow transplant model, colitis model, and liver injury model
Intraperitoneal injection
10 mg/kg
Twice daily for 21 days
To evaluate the promotion of tissue regeneration by SW033291, results showed accelerated hematopoietic recovery after bone marrow transplant and promoted tissue regeneration after colon and liver injury
Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration. Science.
Mice
EP4 knockout mice
Injection
10 mg/kg/day
Once daily for 7 days
To evaluate the effect of SW033291 on bone regeneration, results showed significant promotion of bone formation in EP4wt mice, but the effect was obstructed in EP4 knockout mice
Nat Commun. 2019 Jan 14;10(1):181
Mice
Bone marrow transplantation model
Intraperitoneal injection
5 mg/kg
Twice daily for 5 days
PGDHi, by inhibiting 15-PGDH, increases PGE2 levels in the spleen and bone marrow, promotes homing and regeneration of hematopoietic stem cells, and accelerates hematopoietic recovery after bone marrow transplantation.
JCI Insight. 2021 Mar 22;6(6):e143658
Mice
Bleomycin-induced pulmonary fibrosis model
Intraperitoneal injection
5 mg/kg
Twice daily for 35 days
To evaluate the protective effects of 15-PGDH inhibition on pulmonary fibrosis. Results showed that PGDHi attenuated early inflammation, reduced fibrotic lesions and extracellular matrix remodeling, improved pulmonary function, and decreased mortality.
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