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Basic Research

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

Prostate Cancer and Prostatic Diseases volume 19, pages 21–27 (2016)Cite this article

Subjects

Abstract

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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Acknowledgements

Special thanks to Howard Tearle and Mary Bowden for providing animal care and surgical expertise, and Mitali Pandey for data analysis support. This work is dedicated to the memory of Dr Nicholas Bruchovsky. Funding support provided by the Prostate Cancer Foundation British Columbia to JAG and Prostate Cancer Canada to KMW and MEC (Prostate Cancer Canada Movember Pilot Grant Program #2012-917).

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Authors and Affiliations

  1. Vancouver Prostate Centre, Vancouver Costal Health Research Institute, University of British Columbia, Vancouver, BC, Canada,

    J A Gordon, A Midha, M Ghaffari, H H Adomat, Y Guo, E S Guns & M E Cox

  2. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada,

    J A Gordon, A Midha, A Szeitz, T L Klassen & K M Wasan

  3. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada,

    E S Guns & M E Cox

  4. College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, BC, Canada,

    K M Wasan

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  1. J A Gordon
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Correspondence to K M Wasan or M E Cox.

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Gordon, J., Midha, A., Szeitz, A. et al. Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts. Prostate Cancer Prostatic Dis 19, 21–27 (2016). https://doi.org/10.1038/pcan.2015.37

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