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Piperazine‐designed α 1A /α 1D ‐adrenoceptor blocker KMUP‐1 and doxazosin provide down‐regulation of androgen receptor and PSA in prostatic LNCaP cells growth and specifically in xenografts
Author(s) -
Liu ChiMing,
Lo YiChing,
Tai MingHong,
Wu BinNan,
Wu WenJeng,
Chou YiiHer,
Chai CheeYin,
Huang ChunHsiung,
Chen IngJun
Publication year - 2009
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.20919
Subject(s) - lncap , doxazosin , biology , cell cycle , cell growth , prostate cancer , cancer research , endocrinology , medicine , pharmacology , apoptosis , cancer , biochemistry , blood pressure
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. Prostate 69:610–623, 2009. © 2009 Wiley‐Liss, Inc.

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