ABSTRACT
Title
Novel inhibitors of microsomal prostaglandin E synthase-1 suppress tumor growth and angiogenesis
Authors
E. Terzuoli1, S. Donnini1, F. Finetti1, I. Coletta2, G. Mangano2, A. Giachetti1, L. Polenzani2, M. Ziche1
1Dept of Biotechnology, University of Siena, Italy, 2Angelini Farmaceutici-A.C.R.A.F., Rome, Italy
1Dept of Biotechnology, University of Siena, Italy, 2Angelini Farmaceutici-A.C.R.A.F., Rome, Italy
Abstract
The efficacy of nonsteroidal anti-inflammatory drugs and COX-2 inhibitors has been largely attributed to the inhibition of PGE2 synthesis. Several studies provide the evidence that PGE2 exerts an important pro-tumurogenic action in a number of human and experimental tumors (Eberhart CE et al., 1994; Marnett L J et al., 2002, Menter D G et al., 2010). The formation of PGE2 via COX-1 or COX-2, is catalysed by isomerases, PGE synthases, and mPGES-1, the inducible one has emerged as a potential target for treatment of diseases involving formation of PGE2, such as cancer (Samuelsson B et al., 2007). In this work we describes the properties of two new mPGES-1 inhibitors, AF3433 and AF 3485, and their effect on A431 tumor cells as well on a tumor model in vivo. The compoundsinhibited recombinant human mPGES-1 activity with a high degree of selectivity over other prostanoid synthases. In A431 cells, the compounds (1-10 µM) reduced PGE2 production to basal levels both in quiescent and in cells stimulated by the inflammatory cytokine interleukin-1beta (IL-1b). The compounds alsodecreased the expression of growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). In vivo, in A431 xenograft, AF3433 and AF 3485 administered sub-chronically (0.1-20 mg/kg/mouse), strongly decreased tumor growth. This effect is associated to reduction of tumor microvessel density. In conclusion the data demonstrate that the mPGES-1 inhibitors AF3433 and AF3485 possess an interesting antitumor activity which appears to be associated to an effect on tumor angiogenesis. These results underscorethe potential of mPGES-1 inhibitors as an attractive target for therapeutic intervention.
Eberhart CE et al. (1994). Gastroenterology 107(4):1183-8.
Marnett L J et al. (2002). Annu Rev Pharmacol Toxicol 42:55-80
Menter DG et al. (2010) Clin Cancer Res 16(5):1384-90
Samuelsson B et al. (2007) Pharmacol Rev 59:207-224
Eberhart CE et al. (1994). Gastroenterology 107(4):1183-8.
Marnett L J et al. (2002). Annu Rev Pharmacol Toxicol 42:55-80
Menter DG et al. (2010) Clin Cancer Res 16(5):1384-90
Samuelsson B et al. (2007) Pharmacol Rev 59:207-224