Purpose: To investigate the effects and mechanisms of atorvastatin and celecoxib administered individually or in combination on human prostate cancer PC-3 cells cultured in vitro or grown as xenograft tumors in immunodeficient mice. Experimental Design: Human prostate cancer PC-3 cells in culture were treated with atorvastatin and celecoxib alone or in combination. Severe combined immunodeficient (SCID) mice were injected s.c. with PC-3 cells. The mice received daily i.p injections starting 2 days before tumor cell inoculation and continuing during the course of treatment with atorvastatin (10 Ag/g body weight/d), celecoxib (10 Ag/g/d), a combination of atorvastatin (10 Ag/g/d) and celecoxib (10 Ag/g/d), or a combination of atorvastatin (5 Ag/g/d) and celecoxib (5 Ag/g/d).Results: Atorvastatin in combination with celecoxib had stronger effects on growth inhibition and apoptosis of PC-3 cells than either agent used individually. Atorvastatin and celecoxib in combination also had a stronger inhibitory effect on activation of nuclear factor-nB and extracellular signal-regulated kinase1/2 in PC-3 cells than either agent alone.Treatment of SCID mice with combinations of atorvastatin and celecoxib more effectively inhibited the formation and growth of PC-3 tumors in the mice than either agent administered alone. Conclusions: A combination of atorvastatin and celecoxib had a more potent inhibitory effect on the growth of PC-3 cells cultured in vitro or grown in SCID mice than either agent alone. A combination of atorvastatin and celecoxib may be an effective strategy for the prevention of prostate cancer.Early studies have shown the presence of prostate cancer cells in a large number of men, but in many of these individuals, the cells remain dormant and do not form clinically relevant tumors that kill the individual (1). Why these cells multiply and form lethal metastatic tumors in some individuals but remain dormant in others is an important question. Autopsies of elderly men in Asia and the United States indicated that most elderly men without clinically diagnosed prostate cancer in both Japan and the United States had a high incidence of histologically diagnosed prostate cancer. However, prostate cancer deaths in the United States were considerably higher than in Japan (2 -4). These observations indicate that environmental/lifestyle factors influence the progression of dormant prostate cancer cells to lethal cancers. Prostate cancer cells often invade the bone marrow. These cells remain dormant, and the time between dissemination to evidence of clinically important metastatic disease may be prolonged for more than 10 years (discussed in ref. 5). The mechanism for the activation and growth of dormant prostate cancer cells is unknown. A recent study suggested that a low ratio of phosphorylated extracellular signal-regulated kinase (phospho-Erk)/p38 is associated with dormancy for several cancer cell lines including the PC-3 androgen-independent prostate cancer cell line and that increased phospho-Erk is assoc...

The percentage of animals with some tumor regression after 21 days of treatment was 0% for the control group, 31% for the ATRA group, 62% for the TPA group, and 100% for the TPA؉ATRA group (13 mice/ group). Although treatment of the mice with TPA or TPA؉ATRA continued to inhibit tumor growth for the duration of the 46-day study, treatment of the mice with ATRA alone did not inhibit tumor growth beyond 28 days of daily injections (6 mice/group). Mechanistic studies indicated that treatment of the mice with TPA or TPA؉ATRA for 46 days increased apoptosis in the tumors, and treatment with TPA؉ATRA also decreased the mitotic index. Because the dose of TPA used in this study was effective and resulted in clinically achievable blood levels, clinical trials with TPA alone or in combination with ATRA in patients with prostate cancer may be warranted.

Purpose: To investigate the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate cancer cells cultured in vitro or grown as tumors in immunodeficient mice. Experimental Design: Human prostate cancer LNCaP cells in culture were treated with TPA alone or in combination with paclitaxel. NCr immunodeficient mice with well-established LNCaP tumors received i.p. injections with vehicle or with TPA, paclitaxel, or TPA in combination with paclitaxel. The animals either received daily treatment for 5 consecutive days followed by a 2-day intermission, which was repeated for a total of 28 days (experiment 1), or continuous daily treatment for 28 days (experiment 2).

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The effects of 12-O-tetradecanoylphorbol-13acetate (TPA) alone or in combination with an NF-κB 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-κB 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 wellestablished tumors received daily i.p. injections with TPA (100 ng/g body weight/day), BAY (4 μg/g/day), or a combination of TPA (100 ng/g/day) and BAY (4 μg/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-κB activity is associated with enhanced TPA-induced growth inhibition and apoptosis in PC-3 cells. Inhibition of NF-κB activity by suitable pharmacological inhibitors may be an effective strategy for improving the therapeutic efficacy of TPA in prostate cancer.