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Invest New Drugs ; 30(5): 1865-77, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21931968

RESUMO

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-1ß-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.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Inflamação/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Dinoprostona/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Células HCT116 , Células HT29 , Humanos , Inflamação/metabolismo , Oxirredutases Intramoleculares/metabolismo , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos SCID , Microssomos/metabolismo , Prostaglandina-E Sintases , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas E/farmacologia , Ressonância de Plasmônio de Superfície
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