title: Identification of a novel class of anti-inflammatory compounds with anti-tumor activity in colorectal and lung cancers.
abstract: Chronic inflammation is associated with 25% of all cancers. In the inflammation-cancer axis, prostaglandin E(2) (PGE(2)) is one of the major players. PGE(2) synthases (PGES) are the enzymes downstream of the cyclooxygenases (COXs) in the PGE(2) biosynthesis pathway. Microsomal prostaglandin E(2) synthase 1 (mPGES-1) is inducible by pro-inflammatory stimuli and constitutively expressed in a variety of cancers. The potential role for this enzyme in tumorigenesis has been reported and mPGES-1 represents a novel therapeutic target for cancers. In order to identify novel small molecule inhibitors of mPGES-1, we screened the ChemBridge library and identified 13 compounds as potential hits. These compounds were tested for their ability to bind directly to the enzyme using surface plasmon resonance spectroscopy and to decrease cytokine-stimulated PGE(2) production in various cancer cell lines. We demonstrate that the compound PGE0001 (ChemBridge ID number 5654455) binds to human mPGES-1 recombinant protein with good affinity (K(D) = 21.3 ± 7.8 μM). PGE0001 reduces IL-1β-induced PGE(2) release in human HCA-7 colon and A549 lung cancer cell lines with EC(50) in the sub-micromolar range. Although PGE0001 may have alternative targets based on the results from in vitro assays, it shows promising effects in vivo. PGE0001 exhibits significant anti-tumor activity in SW837 rectum and A549 lung cancer xenografts in SCID mice. Single injection i.p. of PGE0001 at 100 mg/kg decreases serum PGE(2) levels in mice within 5 h. In summary, our data suggest that the identified compound PGE0001 exerts anti-tumor activity via the inhibition of the PGE(2) synthesis pathway.
authors.affiliation: Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Chang
authors.forename: Zuohe
authors.initials: Z
authors.lastname: Song
authors.forename: Lee
authors.initials: L
authors.lastname: Wisner
authors.forename: Tina
authors.initials: T
authors.lastname: Tripp
authors.forename: Vijay
authors.initials: V
authors.lastname: Gokhale
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008861:Microsomes / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011458:Prostaglandins E / Q000494:pharmacology; D020349:Surface Plasmon Resonance
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D011458:Prostaglandins E; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone