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BACKGROUND Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer, but not the incidence of the disease. However, the association of combination therapy in cholesterol reduction on prostate or any cancer is unclear. In this study, we compared the effects of the cholesterol lowering drugs simvastatin and ezetimibe alone or in combination on the growth of LAPC-4 prostate cancer in vivo xenografts. METHODS Proliferation assays were conducted by MTS solution and assessed by Student's t-test. 90 male nude mice were placed on a high-cholesterol Western-diet for 7 days then injected subcutaneously with 1 × 105 LAPC-4 cells. Two weeks post-injection, mice were randomized to control, 11 mg/kg/day simvastatin, 30 mg/kg ezetimibe, or the combination and sacrificed 42 days post-randomization. We used a generalized linear model with the predictor variables of treatment, time, and treatment by time (i.e., interaction term) with tumor volume as the outcome variable. Total serum and tumor cholesterol were measured. Tumoral RNA was extracted and cDNA synthesized from 1 ug of total RNA for quantitative real-time PCR. RESULTS Simvastatin directly reduced in vitro prostate cell proliferation in a dose-dependent, cell line-specific manner, but ezetimibe had no effect. In vivo, low continuous dosing of ezetimibe, delivered by food, or simvastatin, delivered via an osmotic pump had no effect on tumor growth compared to control mice. In contrast, dual treatment of simvastatin and ezetimibe accelerated tumor growth. Ezetimibe significantly lowered serum cholesterol by 15%, while simvastatin had no effect. Ezetimibe treatment resulted in higher tumor cholesterol. A sixfold induction of low density lipoprotein receptor mRNA was observed in ezetimibe and the combination with simvastatin versus control tumors. CONCLUSIONS Systemic cholesterol lowering by ezetimibe did not slow tumor growth, nor did the cholesterol independent effects of simvastatin and the combined treatment increased tumor growth. Despite lower serum cholesterol, tumors from ezetimibe treated mice had higher levels of cholesterol. This study suggests that induction of low density lipoprotein receptor is a possible mechanism of resistance that prostate tumors use to counteract the therapeutic effects of lowering serum cholesterol. Prostate © 2016 Wiley Periodicals, Inc.

Background: Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer (PC), but not the incidence of the disease. This may occur by lowering levels of low-density lipoproteins (LDL). Statins and cholesterol-uptake inhibitors like ezetimibe lower serum LDL and are commonly prescribed for patients with high cholesterol. In this study, we determined the therapeutic role of simvastatin, ezetimibe, or both in vitro using several PC cell lines and in vivo using a LAPC-4 xenograft model. Methods: We treated 4 PC cell lines (LAPC-4, CWR22rv1, PC-3, and DU145) with varying concentrations of simvastatin (0-1000nM) or ezetimibe (0-100μM) for 0-5 days. MTS assays were performed to determine cell proliferation, and the IC50 was calculated using BioDataFit 1.02. For our in vivo study, a total of 90 athymic male nude mice were fed a high-fat, high-cholesterol diet (HFHC; 40% fat, 17% protein, 43% carbohydrates, 1.25% cholesterol), subcutaneously injected with 1 x 10^5 LAPC-4 cells, and randomized 2 weeks later to 1 of 4 treatments: vehicle control, 11mg/kg/day simvastatin (delivered via osmotic pump), 30mg/kg diet ezetimibe (delivered in the food), or simvastatin + ezetimibe. Mice remained on study for 42 days post-randomization, at which point they were harvested and samples analyzed. Results: In vitro, simvastatin directly reduced PC cell proliferation in a dose-dependent, cell line-specific manner, but ezetimibe had no inhibitory effect. In vivo, treatment of low continuous dosing of simvastatin or ezetimibe for 42 days had no effect on tumor growth compared to control. However, relative to control, the combination of simvastatin and ezetimibe accelerated tumor growth (p=0.01). The simvastatin-ezetimibe mice also showed lower fat infiltration in the liver and lower serum cholesterol, but higher tumor cholesterol levels than control. Conclusions: Our results suggest that low continuous dosing of simvastatin or ezetimibe may have no effect on PC growth in a slow-growing LAPC-4 xenograft model, but the combination of simvastatin and ezetimibe may accelerate PC growth, possibly by stimulating cholesterol uptake within the tumor. This novel finding may be important in implementing new treatments for men with slow growing PC and high cholesterol. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3220. doi:1538-7445.AM2012-3220