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.

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. 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. 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. 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.

Liu CM ，Lo YC ，Tai MH ，Wu BN ，Wu WJ ，Chou YH ，Chai CY ，Huang CH ，Chen IJ ... -  《-》

Downregulation of androgen receptor expression by luteolin causes inhibition of cell proliferation and induction of apoptosis in human prostate cancer cells and xenografts.

Androgen receptor (ARs) play a crucial role in the development and progression of prostate cancer. Recent studies have suggested that prostate cancer cell proliferation is inhibited by AR downregulation. Our aim was to investigate how luteolin, a natural flavonoid, affects cell growth and AR expression in prostate cancer cells and xenografts. We assessed prostate cancer cell (LNCaP, DU145, and PC-3) proliferation and apoptosis by MTT assay, flow cytometric analysis, and Western analysis. AR function was measured by evaluating the AR target molecule, prostate-specific antigen (PSA), by RT-PCR, Western blotting, and enzyme-linked immunosorbent assay. We determined the mechanism of AR downregulation with cycloheximide chase assays, proteasome inhibitor, and coimmunoprecipitation experiments. The effects of luteolin on growth inhibition in vivo were examined by LNCaP xenografts in SCID mice. Luteolin significantly repressed prostate cancer cell proliferation and induced apoptosis in LNCaP cells. PC-3 and DU145 cells were less susceptible to luteolin-mediated growth inhibition. Luteolin simultaneously suppressed intracellular and secreted PSA levels and repressed AR mRNA and protein expression in a dose- and time-dependent manner. Luteolin reduced the association between AR and heat-shock protein 90, causing AR degradation through a proteasome-mediated pathway in a ligand-independent manner. Luteolin also suppressed LNCaP xenograft tumor growth in SCID mice. Luteolin-mediated AR downregulation contributes to the inhibition of cell proliferation and the induction of apoptosis in LNCaP human prostate cancer cells, suggesting that AR is a molecular target for luteolin-mediated anticancer activity. Luteolin may act as a chemopreventive or chemotherapeutic agent for prostate cancer.

Chiu FL ，Lin JK 《PROSTATE》

Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis.

Kyprianou N ，Benning CM 《CANCER RESEARCH》

Establishment and characterization of androgen-independent human prostate cancer cell lines, LN-REC4 and LNCaP-SF, from LNCaP.

Iwasa Y ，Mizokami A ，Miwa S ，Koshida K ，Namiki M ... -  《INTERNATIONAL JOURNAL OF UROLOGY》

Monomethylated selenium inhibits growth of LNCaP human prostate cancer xenograft accompanied by a decrease in the expression of androgen receptor and prostate-specific antigen (PSA).

Epidemiological studies and prevention trials suggest selenium is a promising preventive agent for prostate cancer. Selenium-containing compounds inhibited the growth of prostate cancer cell lines including androgen sensitive LNCaP and androgen insensitive DU145 and PC3 cells in vitro. Previous study revealed a novel mechanism of selenium action in which selenium (methylseleninic acid (MSA)) markedly reduced androgen receptor (AR) signaling in prostate cancer cells, suggesting that selenium might act as an antiandrogen, which could serve as a therapeutic agent for prostate cancer. In this study, we tested whether selenium (methylselenocysteine (MSC)) affects tumor growth of human prostate cancer cells by targeting AR signaling in vivo. Prostate tumor xenografts were established in nude mice by co-inoculating LNCaP cells with Matrigel. The mice-bearing tumors were treated with or without MSC (100 microg/mouse/day) via intraperitoneal injection for 2 weeks. The effect of MSC on tumor growth, AR, and prostate-specific antigen (PSA) expression was examined. Methylselenocysteine (MSC) significantly inhibited LNCaP tumor growth (P < 0.05). AR expression in tumor tissues and serum PSA levels were considerably decreased in MSC-treated mice compared to the vehicle controls. Pharmacological dose of MSC inhibits the growth of LNCaP human prostate cancer in vivo accompanied by a decrease in the expression of AR and PSA. These findings suggest that selenium (MSC) can serve as a therapeutic agent aimed at disruption of AR signaling for prostate cancer.

Lee SO ，Yeon Chun J ，Nadiminty N ，Trump DL ，Ip C ，Dong Y ，Gao AC ... -  《PROSTATE》