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Beschreibung

A cell-permeable indolylpyrimidinediamine compound that selectively suppresses upregulation of GTP-bound Rac1 and Cdc42, but not RhoA, in prostate cancer cells upon EGF-stimulation (Effec. Conc. = 20 µ,M in serum-starved 22Rv1, DU 154, PC-3 cultures), resulting in time- and dose-dependent (2 to 10 µ,M and up to 72 h) growth inhibition in serum-deprived cultures with or without EGF stimulation. Dual Cdc42/Rac1 inhibition by AZA1 also effectively inhibits prostate cancer cells migration by decreasing cellular F-/G-actin ratio and disabling both filopodia and lamepodia formation. Daily intraperitoneal injection (100 µ,g/100 µ,L 30% DMSO/mouse) is shown to suppress 22Rv1 tumor expansion in mice in vivo., A cell-permeable indolylpyrimidinediamine compound that selectively suppresses cellular levels of GTP-bound Rac1 and Cdc42, but not RhoA, in serum-starved prostate cancer cultures upon EGF-stimulation (% of non-stimulated control Rac1-GTP level with/without 20 µ,M AZA1 = 56/375 in 22Rv1, 30/235 in DU 154, and 12/118 in PC-3 cells, % of non-EGF-stimulated control Cdc42-GTP level with/without 20 µ,M AZA1 = 15/170 in 22Rv1, 30/105 in DU 154, and 12/100 in PC-3 cells), resulting in effective suppression of PAK1, Akt, and BAD phosphorylations, as well as time- and dose-dependent (2 to 10 µ,M and up to 72 hr) growth inhibition of the cells in serum-deprived cultures with or without EGF stimulation. Dual Cdc42/Rac1 inhibition by AZA1 also effectively inhibits prostate cancer cells migration by decreasing cellular F-/G-actin ratio and disabling both filopodia and lamepodia formation. Daily intraperitoneal injection (100 µ,g/100 µ,L 30% DMSO/mouse) is shown to be efficacious in suppressing 22Rv1 tumor expansion in mice in vivo.