title: Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model.
abstract: 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.
  
  
  
  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 × 105LAPC-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.
  
  
  
  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.
  
  
  
  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 77:446-457, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Masko
authors.affiliation: Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Alfaqih
authors.affiliation: Department of Orthopedic Surgery, Harvard Medical School, Boston, Massachusetts.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Solomon
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: William T
authors.initials: WT
authors.lastname: Barry
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Muehlbauer
authors.affiliation: Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Valilis
authors.affiliation: Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Tameika E
authors.initials: TE
authors.lastname: Phillips
authors.affiliation: Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Poulton
authors.affiliation: Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Alexis R
authors.initials: AR
authors.lastname: Freedland
authors.affiliation: Department of Surgery, Durham Veterans Administration Hospital, Durham, North Carolina.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sun
authors.affiliation: Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Shweta K
authors.initials: SK
authors.lastname: Dambal
authors.affiliation: Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Sanders
authors.affiliation: Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina.|Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Everardo
authors.initials: E
authors.lastname: Macias
authors.affiliation: Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Pizzo
authors.affiliation: Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California.|Department of Surgery, Durham Veterans Administration Hospital, Durham, North Carolina.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Freedland
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002784:Cholesterol / Q000097:blood*; D004359:Drug Therapy, Combination; D000069438:Ezetimibe / Q000008:administration & dosage; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000097:blood* / Q000188:drug therapy; D019821:Simvastatin / Q000008:administration & dosage; D047368:Tumor Burden / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000924:Anticholesteremic Agents; D002784:Cholesterol; D019821:Simvastatin; D000069438:Ezetimibe
keywords: cholesterol; ezetimibe; prostate cancer; simvastatin