title: Ericifolin: a novel antitumor compound from allspice that silences androgen receptor in prostate cancer.
abstract: Silencing of androgen receptor (AR) signaling is a specific and effective mechanism to cure cancer of the prostate (CaP). In this study, the isolation and characterization of a compound from the aromatic berries of Pimenta dioica (allspice) that silences AR is presented. Potential antitumor activities of an aqueous allspice extract (AAE) and a compound purified from the extract were tested on CaP cells. AAE inhibited tumor cell proliferation and colony formation (50% growth inhibition ∼40-85 µg/ml) but not the viability of quiescent normal fibroblasts or non-tumorigenic prostate cells. In tumor cells, AAE inhibited cell cycle progression at G1/S, induced apoptosis or autophagy. Apoptosis was by caspase-dependent poly (ADP ribose) polymerase cleavage. A caspase-independent, apoptosis-inducing factor-mediated mechanism of apoptosis caused cell death in castration-resistant AR-positive or AR-negative CaP cells, such as CWR22RV1, PC-3 or DU145 cells. Treatment with AAE decreased the levels of AR messenger RNA (mRNA), protein and silenced AR activity in AR-positive cells. AR depletion was due to inhibition of AR promoter activity and mRNA stability. Delayed tumor growth (~55%) without measurable systemic toxicity was observed in LNCaP tumor-bearing mice treated with AAE by oral or intraperitoneal routes. LNCaP tumor tissues from AAE-treated mice revealed increased apoptosis as a potential mechanism of antitumor activity of AAE. The chemical identity of bioactive compound in AAE was established through multistep high-performance liquid chromatography fractionation, mass and Nuclear Magnetic Resonance spectroscopies. The compound, eugenol 5-O-β-(6'-galloylglucopyranoside) or ericifolin (EF), showed antiproliferative, pro-apoptosis and anti-AR transcription activities. These results demonstrate a potential use of AAE and EF against prostate cancer.
authors.affiliation: Department of Urology and Sylvester Cancer Center, School of Medicine, University of Miami, FL 33101, USA.
authors.forename: Nagarajarao
authors.initials: N
authors.lastname: Shamaladevi
authors.forename: Dominic A
authors.initials: DA
authors.lastname: Lyn
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Shaaban
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Susana
authors.initials: S
authors.lastname: Villate
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rohr
authors.forename: Bal L
authors.initials: BL
authors.lastname: Lokeshwar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005054:Eugenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D020868:Gene Silencing / Q000187:drug effects*; D006027:Glycosides / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D027841:Pimenta; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D006027:Glycosides; D012333:RNA, Messenger; D011944:Receptors, Androgen; D005054:Eugenol; C521615:ericifolin; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases