Abstract 1520: Simvastatin alters oxysterol profiles in TRAMP mice.

Abstract

Due to mounting epidemiological data evidence, we sought to determine if simvastatin, the most widely used cholesterol lowering medication, could alter prostate cancer incidence in the TRAMP mouse model of prostate cancer. We hypothesized that simvastatin would inhibit advanced prostate cancer formation. Two separate studies were performed using high doses of simvastatin (up to 0.050% w/w) or simvastatin plus genistein in a high fat Western diet. While prostate cancer incidence was only moderately reduced, surprising changes in the serum oxysterol profiles of the TRAMP mice were detected. Oxysterols, oxygenated derivatives of cholesterol, have recently been shown to influence human diseases, and here we suggest that five oxysterols may play a role in prostate cancer progression. Ten mice were chosen from each treatment group, and their serum oxysterol profiles were analyzed by LC-MS-MS. The oxysterol that was most responsive to treatment was 24(S)-hydroxycholesterol, reducing significantly in all treatment groups. 24(S)-OHC was reduced from the control at 20 ng/mL to 10 ng/mL with statin treatment (p-value <0.001). 27-hydroxycholesterol was also reduced in the 0.044% simvastatin w/w dose to 10 ng/mL from 16 ng/mL in the control diet (p-value = 0.025). 5,6-dihydroxycholesterol responded to the 0.044% simvastatin diet lowering to 10 ng/mL as compared to the control of 18 ng/mL (p-value = 0.0002). 4-beta-hydroxycholesterol only responded to a combination of 0.050% simvastatin and 400 mg/kg genistein treatment, lowering from the control of 605 ng/mL down to 340 ng/mL with combination treatment (p-value <0.0001). Lastly 7-keto-cholesterol was reduced by the 0.044% simvastatin treatment, lowering to 44 ng/mL from the control of 67 ng/mL (p-value = 0.004). Future studies will determine how these oxysterols can influence signaling pathways that can affect prostate cancer progression. In summary, we have found an off target effect of simvastatin treatment in TRAMP mice. Although serum cholesterol parameters remain statistically similar, with no observable changes in LDL, HDL, triglycerides, or total cholesterol, serum oxysterol profiles were changed significantly with simvastatin treatment. Potentially one of the pharmacological mechanisms for the beneficial effects of statin treatment on cancer outcomes is not due to their cholesterol lowering abilities, but instead may hinge on their capacity to change the concentration of oxysterols in vivo. Citation Format: Sara K. Drenkhahn, Glenn A. Jackson, Nicholas J.E. Starkey, Yufei Li, Roxanne E. Gelven, Charles E. Wiedmeyer, Jim D. Browning, Kevin L. Fritsche, Cynthia L. Besch-Williford, Dennis B. Lubahn. Simvastatin alters oxysterol profiles in TRAMP mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1520. doi:10.1158/1538-7445.AM2013-1520