Document Detail


Piperazine-designed alpha 1A/alpha 1D-adrenoceptor blocker KMUP-1 and doxazosin provide down-regulation of androgen receptor and PSA in prostatic LNCaP cells growth and specifically in xenografts.
MedLine Citation:
PMID:  19143029     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: KMUP-1 has been suggested to be beneficial in the treatment of benign prostatic hyperplasia. This study is aimed to further investigate whether KMUP-1 and doxazosin prevent from prostate cancer cell growth via androgen-dependent and -independent pathway in vivo and in vitro. METHODS: KMUP-1 was measured the activity on proliferation, apoptosis and cell cycle distribution in prostate cancer cells (LNCaP, DU-145, PC-3) by MTT assay, flow cytometry, Western Blotting and enzyme-linked immunosorbent assay (ELISA). The inhibition activities on androgen receptor (AR) and AR-targeting molecular prostate-specific antigen (PSA) expression by KMUP-1 and doxazosin were measured by RT-PCR, Western Blotting, and ELISA. Furthermore, we confirmed the effects of KMUP-1 on growth of LNCaP xenografts in nude mice. RESULTS: KMUP-1 significantly inhibited LNCaP cell growth and induced apoptosis in time- and dose-dependent manner. KMUP-1 and doxazosin further inhibited the expression of AR and PSA. Treatment of LNCaP cells with KMUP-1 resulted in cell cycle arrest and apoptotic activities, increasing p21 and p27 and decreasing expressions of cyclin D1, cyclin E, cyclin dependent kinase (CDK) 4, CDK2 and CDK6. Moreover, KMUP-1 activated p53, cleaved poly (ADP-ribose) polymerase and caspase-3, but reduced the expression of Bcl-2. Regular administration of KMUP-1 suppressed the LNCaP xenograft tumor growth in nude mice. CONCLUSION: These evidences indicate that KMUP-1 and doxazosin inhibit LNCaP cell growth and downregulate expression of AR and PSA. KMUP-1 might be used as a chemoprevention agent for preventing the development of prostate cancer without cardiovascular adverse effect of doxazosin.
Authors:
Chi-Ming Liu; Yi-Ching Lo; Ming-Hong Tai; Bin-Nan Wu; Wen-Jeng Wu; Yii-Her Chou; Chee-Yin Chai; Chun-Hsiung Huang; Ing-Jun Chen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Prostate     Volume:  69     ISSN:  1097-0045     ISO Abbreviation:  Prostate     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-03-30     Completed Date:  2009-05-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8101368     Medline TA:  Prostate     Country:  United States    
Other Details:
Languages:  eng     Pagination:  610-23     Citation Subset:  IM    
Copyright Information:
(c) 2009 Wiley-Liss, Inc.
Affiliation:
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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MeSH Terms
Descriptor/Qualifier:
Adrenergic alpha-Antagonists / pharmacology*
Animals
Cell Division / drug effects
Down-Regulation
Doxazosin / pharmacology*
Enzyme-Linked Immunosorbent Assay
Humans
Male
Mice
Mice, Nude
Piperidines / pharmacology*
Prostate-Specific Antigen / genetics*
Prostatic Neoplasms / pathology*
Proto-Oncogene Proteins c-bcl-2 / genetics
Receptors, Androgen / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Transplantation, Heterologous
Xanthines / pharmacology*
bcl-2-Associated X Protein / genetics
Chemical
Reg. No./Substance:
0/Adrenergic alpha-Antagonists; 0/KMUP 1; 0/Piperidines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Receptors, Androgen; 0/Xanthines; 0/bcl-2-Associated X Protein; 74191-85-8/Doxazosin; EC 3.4.21.77/Prostate-Specific Antigen

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