We determined the inhibitory effect of dietary atorvastatin, dietary celecoxib and voluntary running wheel exercise (RW) alone or in combination on the formation and growth of androgen-independent LNCaP tumors in castrated SCID mice. Male SCID mice were injected subcutaneously with androgen-dependent prostate cancer LNCaP cells. When the tumors reached a moderate size, the mice were surgically castrated and treated with atorvastatin (0.02% in the diet), celecoxib (0.05% in the diet) or RW alone or in combination for 42 days. RW or celecoxib alone had a moderate inhibitory effect on the androgen-independent growth of LNCaP tumors, but atorvastatin alone had little or no effect on tumor growth. Combinations of atorvastatin and celecoxib had a stronger inhibitory effect on the formation and growth of androgen-independent LNCaP tumors than either drug alone. A combination of RW together with atorvastatin and celecoxib had the most potent inhibitory effect on the progression of LNCaP tumors to androgen independent growth. The serum concentration of atorvastatin after two weeks of oral administration of atorvastatin was 6.1 ng/ml. The serum concentration of celecoxib after treatment with dietary celecoxib for two weeks was 1090 ng/ml. The serum concentration of atorvastatin but not that of celecoxib was substantially reduced when the two drugs were given in combination. The drug concentrations observed in our animal studies are comparable or less than those commonly found in humans treated with atorvastatin or celecoxib. Our results indicate that administration of atorvastatin and celecoxib together with voluntary exercise may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.