Document Detail


Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells.
MedLine Citation:
PMID:  22592999     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Androgen receptor (AR) signaling is regarded as the driving force in prostate carcinogenesis, and its modulation represents a logical target for prostate cancer (PC) prevention and treatment. Natural products are the most consistent source of small molecules for drug development. In this study, we investigate the functional impact of piperlongumine (PL), a naturally occurring alkaloid present in the Long pepper (Piper longum), on AR expression in PC cells and delineate its mechanism of action.
METHODS: Expression and transcriptional activity of AR was examined by western blotting and luciferase reporter assay, respectively. CellTiter Blue assay was utilized to quantify cell proliferation. Reactive oxygen species (ROS) generation was examined by staining cells with a ROS indicator CM-H(2) DCFDA, followed by flow cytometry analysis.
RESULTS: The results of our experiments demonstrate that PL rapidly reduces AR protein levels in PC cells via proteasome-mediated ROS-dependent mechanism. Moreover, PL effectively depletes a modified AR lacking the ligand-binding domain, shedding light on a new paradigm in the treatment approach to prostatic carcinoma that expresses mutated constitutively active AR. Importantly, PL effectively depletes AR in PC cells at low micromolar concentrations, while concurrently exerting a significant inhibitory effect on AR transcriptional activity and proliferation of PC cells.
CONCLUSIONS: Our investigation demonstrates for the first time that PL induces rapid depletion of the AR in PC cells. As such, PL may afford novel opportunities for both prevention and treatment of prostatic malignancy.
Authors:
Konstantin V Golovine; Peter B Makhov; Ervin Teper; Alexander Kutikov; Daniel Canter; Robert G Uzzo; Vladimir M Kolenko
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-05-16
Journal Detail:
Title:  The Prostate     Volume:  73     ISSN:  1097-0045     ISO Abbreviation:  Prostate     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-11-30     Completed Date:  2013-01-29     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  8101368     Medline TA:  Prostate     Country:  United States    
Other Details:
Languages:  eng     Pagination:  23-30     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / drug therapy*,  metabolism,  pathology
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dioxolanes / pharmacology*
Down-Regulation / drug effects
Drug Screening Assays, Antitumor
Gene Expression / drug effects
Humans
Male
Oxidative Stress / drug effects
Prostatic Neoplasms / drug therapy*,  metabolism,  pathology
Proteasome Endopeptidase Complex / drug effects,  metabolism
Reactive Oxygen Species / metabolism
Receptors, Androgen / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
P30 CA006927/CA/NCI NIH HHS; R01 CA134463/CA/NCI NIH HHS; R01 CA134463/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Dioxolanes; 0/Reactive Oxygen Species; 0/Receptors, Androgen; EC 3.4.25.1/Proteasome Endopeptidase Complex; HN39MC8KIO/piperlonguminine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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