Chronic inflammation is associated with 25% of all cancers. In the inflammation-cancer axis, prostaglandin E2 (PGE2) is one of the major players involved. Prostaglandin E synthase (PGES) is an enzyme downstream of the cyclooxygenases (COXs) in the PGE2 biosynthesis pathway. Among the three PGES isoforms, microsomal prostaglandin E synthase-1 (mPGES-1) is inducible by proinflammatory stimuli and constitutively expressed in colon, lung, and gastric cancers. The potential role for this enzyme in tumorigenesis has also been reported. Since inhibition of COXs may lead to some side effects due to the global reduction of other key prostaglandins, targeting downstream mPGES-1 might be a better therapeutic or chemopreventive strategy for cancers. In order to identify novel small molecule inhibitors of mPGES-1, we have screened in silico a small library of compounds. As a result, 14 lead compounds were identified by molecular docking simulations of the chemicals based on the crystal structure of mPGES-1. These compounds were tested for their ability to inhibit cell growth, induce apoptosis and decrease cytokine-stimulated PGE2 production in various colorectal and lung cancer cell lines. Using surface plasmon resonance (SPR) spectroscopy, we show the binding of the compounds PGE001 and PGE011 to human mPGES-1 recombinant protein with good affinity (KD at low micromolar range). These two compounds also showed the ability to reduce the IL-1beta-induced PGE2 production in HT29 and SW837 colon cancer cells and A549 lung cancer cell line with EC50 at low micromolar range. Furthermore, the compounds exhibit significant anti-tumor activity in the SW837 xenograft mouse model with T/C (relative size of treated and control tumors)=40.3% for compound PGE001 and T/C=68.7% for compound PGE011 (P<0.05), when injected i.p. at 200 mg/kg for 5 and 10 days, respectively. When tested daily i.p. for 5 days at 100mg/kg in A549 lung cancer xenografts, the PGE001 showed anti-tumor activity with T/C=67% (P<0.05). In summary, our data suggest that the identified compounds exert their anti-tumor activity through selective binding and inhibition of the enzyme mPGES-1 in the PGE2 synthesis pathway.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3565.