Journal
PROSTATE CANCER AND PROSTATIC DISEASES
Volume 19, Issue 1, Pages 21-27Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/pcan.2015.37
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Funding
- Prostate Cancer Foundation British Columbia
- Prostate Cancer Canada (Prostate Cancer Canada Movember Pilot Grant Program) [2012-917]
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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.
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