Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts

Background:growing evidence supports the idea that de novo steroidogenesis has an important role in prostate cancer’s progression to the castration-resistant state following androgen deprivation therapy. therefore, reducing the availability of cholesterol for use as a precursor in androgen synthesis may reduce proliferation and disease progression.methods:lncap xenograft-bearing mice were castrated and administered simvastatin via diet, and tumor volume and psa concentration were monitored for 8 weeks post castration. levels of serum and intratumoral androgens along with serum simvastatin and common toxicity markers were measured at end point.results:reduced post-castration tumor growth rate in simvastatin-treated mice correlated with delayed time to castration-resistant progression, determined by two serum psa doublings from post-castration nadir, when compared with xenografts in mice on control diet. at 8 weeks post castration, serum simvastatin levels were comparable to clinically relevant human doses with no evidence of overt muscle or liver toxicity. this suppressed post-castration tumor growth in the simvastatin diet group was correlated with reduced intratumoral testosterone and dihydrotestosterone levels.conclusions:reduced tumor growth and intratumoral androgen levels observed in simvastatin-treated, castrated mice harboring lncap xenograft suggests that suppressing de novo steroidogenesis can delay castration-resistant progression of this tumor model.