Effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination with paclitaxel (Taxol) on prostate cancer LNCaP cells cultured in vitro or grown as xenograft tumors in immunodeficient mice

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). Results: Treatment of LNCaP cells with a combination of TPA and paclitaxel synergistically inhibited the growth and induced apoptosis in cultured LNCaP cells, and this treatment also induced a marked increase in phosphorylated c-Jun-NH₂-kinase (JNK). In animal experiments, tumor growth occurred in all mice treated with vehicle. When treated with TPA alone, the percentage of animals with some tumor regression was 33% in experiment 1 and 100% in experiment 2. Treatment of animals with paclitaxel alone caused some tumor regression in 17% and 57% of the animals in experiments 1 and 2, respectively. All animals treated with TPA + paclitaxel in both experiments had some tumor regression. Conclusions: TPA and paclitaxel in combination had a stronger inhibitory effect on the growth of LNCaP cells in culture or as xenograft tumors in immunodeficient mice than either agent alone. Clinical trials with TPA alone or in combination with paclitaxel in patients with prostate cancer may be warranted.