Pro-apoptotic actions of exisulind and CP461 in SW480 colon tumor cells involve β-catenin and cyclin D1 down-regulation

Exisulind and its analogues are inhibitors of cyclic GMP phosphodiesterases (PDEs) that have been shown to activate and induce protein kinase G, resulting in the induction of apoptosis in colon cancer cells. These drugs also reduce β-catenin protein levels and decrease cyclin D1 mRNA levels in SW480 cells. Herein we report on studies pertaining to exisulind regulation of β-catenin levels and activity in colon tumor cells. Exisulind and its higher-affinity PDE analogues, ( Z)-5-fluoro-2-methyl-(4-pyridylidene)-3-( N-benzyl)-indenylacetamide hydrochloride (CP461) and ( Z)-1 H-indene-3-acetamide, 5-fluoro-2-methyl- N-(phenylmethyl)-1-[(3,4,5-trimethoxyphenyl)methylene] (CP248), reduced β-catenin, including the nuclear β-catenin in SW480 cells ( ec 50≈200 μM, 1 μM, and