Combined inhibitory effects of green tea polyphenols and selective cyclooxygenase-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo.

Purpose: Cyclooxygenase-2 (COX-2) inhibitors hold promise for cancer chemoprevention; however, recent toxicity concerns suggest that new strategies are needed. One approach to overcome this limitation is to use lower doses of COX-2 inhibitors in combination with other established agents with complementary mechanisms. In this study, the effect of (−)epigallocatechin-3-gallate (EGCG), a promising chemopreventive agent from green tea, was tested alone and in combination with specific COX-2 inhibitors on the growth of human prostate cancer cells both in vitro and in vivo . Experimental Design: Human prostate cancer cells LNCaP, PC-3, and CWR22Rν1 were treated with EGCG and NS398 alone and in combination, and their effect on growth and apoptosis was evaluated. In vivo , athymic nude mice implanted with androgen-sensitive CWR22Rν1 cells were given green tea polyphenols (0.1% in drinking water) and celecoxib (5 mg/kg, i.p., daily, 5 days per week), alone and in combination, and their effect on tumor growth was evaluated. Results: Combination of EGCG (10-40 μmol/L) and NS-398 (10 μmol/L) resulted in enhanced ( a ) cell growth inhibition; ( b ) apoptosis induction; ( c ) expression of Bax, pro-caspase-6, and pro-caspase-9, and poly(ADP)ribose polymerase cleavage; ( d ) inhibition of peroxisome proliferator activated receptor γ; and ( e ) inhibition of nuclear factor-κB compared with the additive effects of the two agents alone, suggesting a possible synergism. In vivo , combination treatment with green tea polyphenols and celecoxib resulted in enhanced ( a ) tumor growth inhibition, ( b ) lowering of prostate-specific antigen levels, ( c ) lowering of insulin-like growth factor-I levels, and ( d ) circulating levels of serum insulin-like growth factor binding protein-3 compared with results of single-agent treatment. Conclusions: These data suggest synergistic and/or additive effects of combinatorial chemopreventive agents and underscore the need for rational design of human clinical trials.