Inhibition of NF-κB by (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY11-7082; BAY) is associated with enhanced 12-O-tetradecanoylphorbol-13-acetate-induced growth suppression and apoptosis in human prostate cancer PC-3 cells

Abstract

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) alone or in combination with an NF-kappaB inhibitor, (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY 11-7082; BAY), on the growth and apoptosis of human prostate cancer PC-3 cells cultured in vitro or grown in immunodeficient mice were studied. Treatment of cultured PC-3 cells with TPA (0.2-10 ng/ml) for 96 h resulted in growth inhibition and apoptosis in a concentration-dependent manner. BAY inhibited NF-kappaB activity in PC-3 cells as determined by a luciferase reporter assay and enhanced TPA-induced growth inhibition and apoptosis in cultured PC-3 cells. In animal studies, NCr immunodeficient mice were injected subcutaneously with PC-3 cells in Matrigel. Mice with well-established tumors received daily i.p. injections with TPA (100 ng/g body weight/day), BAY (4 microg/g/day), or a combination of TPA (100 ng/g/day) and BAY (4 microg/g/day) for 36 days. Tumor growth occurred in all of the vehicle-treated control mice. The percent of animals with some tumor regression after 36 days of treatment was 0% for the control group, 40% for the TPA group, 50% for the BAY group and 100% for the TPA + BAY group. Mechanistic studies indicated that treatment of the mice with TPA or TPA + BAY decreased proliferation and increased apoptosis in the tumors. Results from our studies indicate that inhibition of NF-kappaB activity is associated with enhanced TPA-induced growth inhibition and apoptosis in PC-3 cells. Inhibition of NF-kappaB activity by suitable pharmacological inhibitors may be an effective strategy for improving the therapeutic efficacy of TPA in prostate cancer.