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

Autor: Gordon JA; Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Midha A; Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Szeitz A; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Ghaffari M; Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada., Adomat HH; Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada., Guo Y; Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada., Klassen TL; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada., Guns ES; Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada., Wasan KM; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.; College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, BC, Canada., Cox ME; Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.; Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
Jazyk: angličtina
Zdroj: Prostate cancer and prostatic diseases [Prostate Cancer Prostatic Dis] 2016 Mar; Vol. 19 (1), pp. 21-7. Date of Electronic Publication: 2015 Aug 04.
DOI: 10.1038/pcan.2015.37
Abstrakt: 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.
Databáze: MEDLINE
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