In vitro activity: SMIP004, a N-(4-butyl-2-methyl-phenyl) acetamide, is a novel specific inducer of cancer-cell selective apoptosis of human prostate cancer cells. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, inhibition of colony formation in soft agar, and cell death. However, the mechanism of SMIP004-induced cancer cell selective apoptosis remained unknown. SMIP004 potently inhibits the growth of prostate and breast cancer xenografts in mice. Our data suggest that SMIP004, by inducing mitochondrial ROS formation, targets specific sensitivities of prostate cancer cells to redox and bioenergetic imbalances that can be exploited in cancer therapy.

Kinase Assay: SMIP004, a N-(4-butyl-2-methyl-phenyl) acetamide, is a novel specific inducer of cancer-cell selective apoptosis of human prostate cancer cells.

Cell Assay: Whereas SMIP012 and 016 were moderately toxic in normal fibroblasts, SMIPs 001 and 004 showed substantial cancer cell specificity being at least five times more potent in LNCaP-S14 than in IMR90 cells , treatment with either MG132 or SMIP004 increased p27 half-life to> 6 h. SMIP004 also reduced the amounts of cyclins E and A retrieved with CDK2. This was paralleled by a marked downregulation of cyclins E and A upon SMIP004 treatment. SMIP004 decreased the levels of positive cell cycle regulators, upregulated cyclin-dependent kinase inhibitors, and resulted in G1 arrest, inhibition of colony formation in soft agar, and cell death.