| 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. | |
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MedLine Citation:
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PMID: 19143029 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Prostate Volume: 69 ISSN: 1097-0045 ISO Abbreviation: Prostate Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-03-30 Completed Date: 2009-05-14 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8101368 Medline TA: Prostate Country: United States |
Other Details:
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Languages: eng Pagination: 610-23 Citation Subset: IM |
Copyright Information:
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(c) 2009 Wiley-Liss, Inc. |
Affiliation:
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Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adrenergic alpha-Antagonists
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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:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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