title: Lupeol, a novel androgen receptor inhibitor: implications in prostate cancer therapy.
abstract: OBJECTIVE
  Conventional therapies to treat prostate cancer (CaP) of androgen-dependent phenotype (ADPC) and castration-resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify those agents that could target AR for both disease types. We provide mechanism-based evidence that lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of androgen receptor (AR) in vitro and in vivo.
  
  
  METHODS
  Normal prostate epithelial cell (RWPE-1), LAPC4 (wild functional AR/ADPC), LNCaP (mutant functional/AR/ADPC), and C4-2b (mutant functional/AR/CRPC) cells were used to test the anti-AR activity of lupeol. Cells grown under androgen-rich environment and treated with lupeol were tested for proliferation, AR transcriptional activity, AR competitive ligand binding, AR-DNA binding, and AR-ARE/target gene binding. Furthermore, in silico molecular modeling for lupeol-AR binding was done. Athymic mice bearing C4-2b and LNCaP cell-originated tumors were treated intraperitoneally with lupeol (40 mg/kg; 3 times/wk) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, lupeol serum levels were measured.
  
  
  RESULTS
  Lupeol significantly inhibited R1881 (androgen analogue) induced (i) transcriptional activity of AR and (ii) expression of PSA. Lupeol (i) competed antagonistically with androgen for AR, (ii) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK, and IL-6, and (iii) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to antihormone therapy. High-performance liquid chromatography analysis showed that lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels.
  
  
  CONCLUSIONS
  Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP.
authors.affiliation: Section of Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, USA.
authors.forename: Hifzur Rahman
authors.initials: HR
authors.lastname: Siddique
authors.forename: Shrawan Kumar
authors.initials: SK
authors.lastname: Mishra
authors.forename: R Jeffery
authors.initials: RJ
authors.lastname: Karnes
authors.forename: Mohammad
authors.initials: M
authors.lastname: Saleem
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D053978:Pentacyclic Triterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017430:Prostate-Specific Antigen / Q000097:blood / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D012319:RNA Polymerase II / Q000378:metabolism; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays; D000094042:Lupanes
chemical_list: D059002:Androgen Receptor Antagonists; D053978:Pentacyclic Triterpenes; D017430:Prostate-Specific Antigen; D012319:RNA Polymerase II; D011944:Receptors, Androgen; C010480:lupeol; D000094042:Lupanes