CAY10404 is a Highly Selective COX-2 Inhibitor
Posted On 2020-09-04
Clooxygenase (COX) is an enzyme responsible for the formation of prostaglandins from arachidonic acid, including thromboxanes and prostaglandins. Specifically, it is a member of the animal heme peroxidase family, also known as prostaglandin G/H synthase. Besides, cyclooxygenase-2 is a candidate gene for lung injury induced by mechanical ventilation. COX-2 is an inducible enzyme that catalyzes the conversion of arachidonic acid to downstream prostaglandins involved in inflammation and vascular homeostasis. Moreover, COX-2 induces increased expression of prostaglandins, which play a key role in regulating inflammation, controlling pulmonary vascular tension, and barrier function. Furthermore, COX-2 plays an important role in the treatment of pulmonary inflammation. And the reduced COX-2 activity is associated with the pathogenesis of pulmonary fibrosis in human and animal models. The role of COX-2 in tumorigenesis involves regulating apoptosis, increasing angiogenesis, regulating immune response, and increasing invasiveness. CAY10404 is a potent and highly selective COX-2 inhibitor.
CAY10404 is a potent and highly selective cyclooxygenase-2 (COX-2) inhibitor.
But, how does CAY10404 protect against cancer cells via COX-2? Let’s discuss it in detail. In the beginning, CAY10404 is a potent and highly selective cyclooxygenase-2 (COX-2) inhibitor with an IC50 of 1 nM. Meanwhile, CAY10404 exhibits no inhibition of COX-1 (IC50>500 µM). Meanwhile, CAY10404 is a potent inhibitor of PKB/Akt and MAPK signaling pathways and induces apoptosis in NSCLC cells. CAY10404, a diarylisoxazole, has good analgesic, anti-inflammatory, and anti-cancer activities.
In the second place, CAY10404 is a potent and selective COX-2 inhibitor with a selectivity index (SI; COX-1 IC50/COX-2 IC50) of >500000. Interestingly, CAY10404 (10-100 µM) inhibits the growth of NSCLC cell lines in a concentration-dependent manner and has an IC50s of 60-100 µM. Importantly, CAY10404 (20-100 µM) induces apoptosis in NSCLC cells. CAY10404 induces a concentration-dependent decrease in the level of the anti-apoptotic proteins (Bcl-2 and Bcl-XL) and pAkt and pGSK-3β. Particularly, CAY10404 does not change the level of the pro-apoptotic protein (Bax) and total Akt and GSK-3β protein levels.
Last but not the least, CAY10404 (50 mg/kg/day) decreases lung inflammation in HTV mice and attenuates ventilator-induced lung injury for 4 days. Obviously, CAY10404 Attenuates cyclooxygenase activity, significantly decreasing BAL PGE2 and 6-keto PGF1α.
All in all, CAY10404 is a potent and highly selective COX-2 inhibitor.
Yongseon Cho, et al. Respirology. 2009 Aug;14(6):850-8.