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Sample records for androgen independent prostate

  1. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Shtutman Michael

    2010-04-01

    Full Text Available Abstract Background Castration resistant prostate cancer (CRPC develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI prostate cancer cells. Results Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881 restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to

  2. LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth and invasion

    OpenAIRE

    Li, Yirong; Wang, Longgui; Zhang, Miao; Melamed, Jonathan; Liu, Xiaomei; Reiter, Robert; Wei, Jianjun; Peng, Yi; Zou, Xuanyi; Pellicer, Angel; Garabedian, Michael J.; Ferrari, Anna; Lee, Peng

    2009-01-01

    A major obstacle in treating prostate cancer is the development of androgen-independent disease. In this study, we examined LEF1 expression in androgen-independent cancer as well as its regulation of androgen receptor (AR) expression, prostate cancer growth and invasion in androgen-independent prostate cancer cells. Affymetrix microarray analysis of LNCaP and LNCaP-AI (androgen-independent variant LNCaP) cells revealed 100-fold increases in LEF1 expression in LNCaP-AI cells. We showed that LE...

  3. Expression of a hyperactive androgen receptor leads to androgen-independent growth of prostate cancer cells.

    Science.gov (United States)

    Hsieh, Chen-Lin; Cai, Changmeng; Giwa, Ahmed; Bivins, Aaronica; Chen, Shao-Yong; Sabry, Dina; Govardhan, Kumara; Shemshedini, Lirim

    2008-07-01

    Cellular changes that affect the androgen receptor (AR) can cause prostate cancer to transition from androgen dependent to androgen independent, which is usually lethal. One common change in prostate tumors is overexpression of the AR, which has been shown to lead to androgen-independent growth of prostate cancer cells. This led us to hypothesize that expression of a hyperactive AR would be sufficient for androgen-independent growth of prostate cancer cells. To test this hypothesis, stable lune cancer prostate (LNCaP) cell lines were generated, which express a virion phosphoprotein (VP)16-AR hybrid protein that contains full-length AR fused to the strong viral transcriptional activation domain VP16. This fusion protein elicited as much as a 20-fold stronger transcriptional activity than the natural AR. Stable expression of VP16-AR in LNCaP cells yielded androgen-independent cell proliferation, while under the same growth conditions the parental LNCaP cells exhibited only androgen-dependent growth. These results show that expression of a hyperactive AR is sufficient for androgen-independent growth of prostate cancer cells. To study the molecular basis of this enhanced growth, we measured the expression of soluble guanylyl cyclase-alpha1 (sGCalpha1), a subunit of the sGC, an androgen-regulated gene that has been shown to be involved in prostate cancer cell growth. Interestingly, the expression of sGCalpha1 is androgen independent in VP16-AR-expressing cells, in contrast to its androgen-induced expression in control LNCaP cells. RNA(I)-dependent inhibition of sGCalpha1 expression resulted in significantly reduced proliferation of VP16-AR cells, implicating an important role for sGCalpha1 in the androgen-independent growth of these cells. PMID:18469090

  4. Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells

    OpenAIRE

    Shtutman Michael; Tanner Matthew J; Carkner Richard D; Baghel Prateek S; Levina Elina; Feuerstein Michael A; Chen Mengqian; Vacherot Francis; Terry Stéphane; de la Taille Alexandre; Buttyan Ralph

    2010-01-01

    Abstract Background Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC....

  5. Development of the VCaP Androgen Independent Model of Prostate Cancer

    OpenAIRE

    Loberg, Robert D; St. John, Lauren N; Day, LaShon L.; Neeley, Chris K; Kenneth J. Pienta

    2006-01-01

    Prostate epithelial cell growth is dependent on the presence of androgens and the transition of prostate cancer to an androgen independent phenotype results in a highly aggressive, currently incurable cancer. We have developed a new preclinical model of androgen independent prostate cancer derived from the VCaP prostate cancer epithelial cell line. VCaP cells were subcutaneously implanted and serially passaged in castrated male SCID mice. Androgen independence was confirmed by WST-1 (a tetraz...

  6. Oncogenic herpesvirus HHV-8 promotes androgen-independent prostate cancer growth.

    Science.gov (United States)

    Mygatt, Justin G; Singhal, Adit; Sukumar, Gauthaman; Dalgard, Clifton L; Kaleeba, Johnan A R

    2013-09-15

    Mechanisms underlying progression to androgen-independent prostate cancer following radical ablation therapy remain poorly defined. Although intraprostatic infections have been highlighted as potential cofactors, pathogen influences on pathways that support tumor regrowth are not known. To explore this provocative concept, we derived androgen-sensitive and -insensitive prostate epithelial cells persistently infected with human herpesvirus 8 (HHV-8), an oncogenic herpesvirus that has been detected in normal prostate epithelium, prostate adenocarcinoma, and biologic fluids of patients with prostate cancer, to explore its effects on transition to hormone-refractory disease. Strikingly, we found that HHV-8 infection of androgen-sensitive prostate cancer cells conferred the capacity for androgen-independent growth. This effect was associated with altered expression and transcriptional activity of the androgen receptor (AR). However, HHV-8 infection bypassed AR signaling by promoting enhancer of zeste homolog 2 (EZH2)-mediated epigenetic silencing of tumor-suppressor genes, including MSMB and DAB2IP that are often inactivated in advanced disease. Furthermore, we found that HHV-8 triggered epithelial-to-mesenchymal transition. Although HHV-8 has not been linked etiologically to prostate cancer, virologic outcomes revealed by our study provide mechanistic insight into how intraprostatic infections could constitute risk for progression to androgen-independent metastatic disease where EZH2 has been implicated. Taken together, our findings prompt further evaluations of the relationship between HHV-8 infections and risk of advanced prostate cancer. PMID:24005834

  7. Glutathione S-transferase Pi mediates proliferation of androgen-independent prostate cancer cells

    OpenAIRE

    Hokaiwado, Naomi; Takeshita, Fumitaka; Naiki-Ito, Aya; Asamoto, Makoto; Ochiya, Takahiro; Shirai, Tomoyuki

    2008-01-01

    Prostate cancers generally acquire an androgen-independent growth capacity with progression, resulting in resistance to antiandrogen therapy. Therefore, identification of the genes regulated through this process may be important for understanding the mechanisms of prostate carcinogenesis. We here utilized androgen-dependent/independent transplantable tumors, newly established with the ‘transgenic rat adenocarcinoma in prostate’ (TRAP) model, to analyze their gene expression using microarrays....

  8. PROGRESSION TO ANDROGEN-INDEPENDENT LNCAP HUMAN PROSTATE TUMORS: CELLULAR AND MOLECULAR ALTERATIONS

    OpenAIRE

    Zhou, Jin-Rong; Yu, Lunyin; Zerbini, Luiz F.; Libermann, Towia A.; Blackburn, George L.

    2004-01-01

    Lethal phenotypes of human prostate cancer are characterized by progression to androgen-independence and metastasis. For want of a clinically relevant animal model, mechanisms behind this progression remain unclear. Our study used an in vivo model of androgen-sensitive LNCaP human prostate cancer cell xenografts in male SCID mice to study the cellular and molecular biology of tumor progression. Primary tumors were established orthotopically, and the mice were then surgically castrated to with...

  9. Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage

    Institute of Scientific and Technical Information of China (English)

    Yuting Lin; Junichi Fukuchi; Richard A Hiipakka; John M Kokontis; Jialing Xiang

    2007-01-01

    Bcl-2 is an anti-apoptotic oncoprotein and its protein levels are inversely correlated with prognosis in many cancers.However, the role of Bcl-2 in the progression of prostate cancer is not clear. Here we report that Bcl-2 is required for the progression of LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. The mRNA and protein levels of Bcl-2 are significantly increased in androgen-independent prostate cancer cells, shRNA-mediated gene silencing of Bcl-2 in androgen-independent prostate cancer cells promotes UV-induced apoptosis and suppresses the growth of prostate tumors in vivo. Growing androgen-dependent cells under androgen-deprivation conditions results in formation of androgen-independent colonies; and the transition from androgen-dependent to androgen-independent growth is blocked by ectopic expression of the Bcl-2 antagonist Bax or Bcl-2 shRNA. Thus, our results demonstrate that Bcl-2 is not only critical for the survival of androgen-independent prostate cancer cells, but is also required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage.

  10. The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

    International Nuclear Information System (INIS)

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPARγ ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPARγ. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPARγ and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  11. The role of mesenchymal stem cells in promoting the transformation of androgen-dependent human prostate cancer cells into androgen-independent manner

    OpenAIRE

    Jiwen Cheng; Keqin Yang; Qingyun Zhang; Yang Yu; Qinggui Meng; Ning Mo; Yang Zhou; Xianlin Yi; Chengzhong Ma; Aming Lei; Yan Liu

    2016-01-01

    Mesenchymal stem cells (MSCs) play an important role in the development of human prostate cancer (PCa). However, the role of MSCs in the transformation of androgen-dependent human PCa cells into androgen-independent manner has been poorly understood. In this study, we investigated the underlying mechanism of MSCs in promoting PCa cells from androgen-dependent into androgen-independent manner. Firstly, we demonstrated that MSCs could affect the transformation of androgen-dependent human PCa ce...

  12. Carmustine enhances the anticancer activity of selenite in androgen-independent prostate cancer cells

    International Nuclear Information System (INIS)

    Apoptosis is one of the major mechanisms targeted in the development of therapies against various cancers, including prostate cancer. Resistance to chemotherapy poses a significant problem for the effective treatment of androgen-independent (hormone-refractory) prostate cancer. Although high concentrations of sodium selenite exert strong anticarcinogenic effects in several cell culture systems and animal models, the therapeutic potential of selenite in patients with advanced or metastatic prostate cancer is extremely limited by the genotoxicity of high-dose selenite. We examined the ability of nontoxic concentrations of selenite to promote apoptosis and inhibit proliferation in carmustine-sensitized androgen-independent human prostate cancer cells. Androgen-dependent LNCaP cells exhibited a significant decrease in cell viability when exposed to nontoxic concentrations of selenite, whereas androgen-independent PC-3 and DU145 cells showed a significant decrease in cell viability only at higher concentrations. Treatment of PC-3 cells with a combination of nontoxic selenite and carmustine resulted in greater increases in cytotoxicity, reactive oxygen species generation, growth inhibition, apoptosis, and DNA double-strand breaks, with concomitant decreases in DNA synthesis, glutathione, glutathione reductase, and antiapoptotic proteins. Combination treatment with carmustine and selenite triggered caspase-dependent apoptosis in PC-3 cells, which was not apparent when these cells were treated with selenite or carmustine alone. Genotoxicity in normal prostate epithelial cells was completely absent in the combination treatment of carmustine and selenite. In addition, carmustine decreased the induction of DNA double strand breaks by high-dose selenite in normal prostate epithelial cells. This is the first study to demonstrate that a nontoxic dose of selenite, in combination with carmustine, significantly induces apoptosis and growth inhibition in androgen-independent

  13. Arsenic trioxide enhances the radiation sensitivity of androgen-dependent and -independent human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Hui-Wen Chiu

    Full Text Available Prostate cancer is the most common malignancy in men. In the present study, LNCaP (androgen-sensitive human prostate cancer cells and PC-3 cells (androgen-independent human prostate cancer cells were used to investigate the anti-cancer effects of ionizing radiation (IR combined with arsenic trioxide (ATO and to determine the underlying mechanisms in vitro and in vivo. We found that IR combined with ATO increases the therapeutic efficacy compared to individual treatments in LNCaP and PC-3 human prostate cancer cells. In addition, combined treatment showed enhanced reactive oxygen species (ROS generation compared to treatment with ATO or IR alone in PC-3 cells. Combined treatment induced autophagy and apoptosis in LNCaP cells, and mainly induced autophagy in PC-3 cells. The cell death that was induced by the combined treatment was primarily the result of inhibition of the Akt/mTOR signaling pathways. Furthermore, we found that the combined treatment of cells pre-treated with 3-MA resulted in a significant change in AO-positive cells and cytotoxicity. In an in vivo study, the combination treatment had anti-tumor growth effects. These novel findings suggest that combined treatment is a potential therapeutic strategy not only for androgen-dependent prostate cancer but also for androgen-independent prostate cancer.

  14. Analysis of the molecular networks in androgen dependent and independent prostate cancer revealed fragile and robust subsystems.

    Directory of Open Access Journals (Sweden)

    Ryan Tasseff

    Full Text Available Androgen ablation therapy is currently the primary treatment for metastatic prostate cancer. Unfortunately, in nearly all cases, androgen ablation fails to permanently arrest cancer progression. As androgens like testosterone are withdrawn, prostate cancer cells lose their androgen sensitivity and begin to proliferate without hormone growth factors. In this study, we constructed and analyzed a mathematical model of the integration between hormone growth factor signaling, androgen receptor activation, and the expression of cyclin D and Prostate-Specific Antigen in human LNCaP prostate adenocarcinoma cells. The objective of the study was to investigate which signaling systems were important in the loss of androgen dependence. The model was formulated as a set of ordinary differential equations which described 212 species and 384 interactions, including both the mRNA and protein levels for key species. An ensemble approach was chosen to constrain model parameters and to estimate the impact of parametric uncertainty on model predictions. Model parameters were identified using 14 steady-state and dynamic LNCaP data sets taken from literature sources. Alterations in the rate of Prostatic Acid Phosphatase expression was sufficient to capture varying levels of androgen dependence. Analysis of the model provided insight into the importance of network components as a function of androgen dependence. The importance of androgen receptor availability and the MAPK/Akt signaling axes was independent of androgen status. Interestingly, androgen receptor availability was important even in androgen-independent LNCaP cells. Translation became progressively more important in androgen-independent LNCaP cells. Further analysis suggested a positive synergy between the MAPK and Akt signaling axes and the translation of key proliferative markers like cyclin D in androgen-independent cells. Taken together, the results support the targeting of both the Akt and MAPK

  15. The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

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    Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

    2010-12-10

    The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

  16. Growth inhibiting effects of terazosin on androgen-independent prostate cancer cell lines

    Institute of Scientific and Technical Information of China (English)

    许克新; 王向红; 凌明达; 王云川

    2003-01-01

    Objective To study the effects of an α1-adrenoceptor antagonist, terazosin on the androgen-independent prostate cancer cell lines PC-3 and DU145.Methods Two androgen independent cell lines, PC-3 and DU145, were used to determine cell viability, colony-forming ability, as well as cell cycle distribution, after exposure to terazosin. Western blot analysis was used to determine the expression of p21WAF1 and p27KIP1.Results This study shows that terazosin inhibits not only prostate cancer cell growth but also its colony forming ability, both of which are main targets of clinical treatment. In addition, terazosin is shown to inhibit cell growth through G1 phase cell cycle arrest and the up-regulation of p27KIP1.Conclusion This study provides evidence that the α1-adrenoceptor antagonist terazosin may have therapeutic potential in the treatment of advanced hormone refractory prostate cancer.

  17. Effect of miR-296 on the Apoptosis of Androgen-independent Prostate Cancer Cells

    Institute of Scientific and Technical Information of China (English)

    Pei CHENG; Run-sheng LI; Biao-yang LIN; Wei-qun WANG; Yu-hua LI; Yan GUO; Wei LI

    2009-01-01

    Objective To investigate the miR-296's function in prostate carcinoma(PCa) cells. Methods In order to profile the miRNA expression in LNCaP cells, the cultured cells were stimulated with androgen after 48-h starvation, miRNA microarray analysis and Q-RT-PCR assay were performed. To characterize the effects of miR296 on PCa cells, CL-1 and PC-3 cells were transfected with miR-296 and antisense-miR-296, cell growth and apoptosis were then analyzed. Results The miR-296-5p expression was up-regulated by 2.22 folds in the CL-1 cells, which do not express significantly androgen receptor, than in LNCaP cells. Knockdown of miR-296-Sp induced apoptosis of CL-1 cells, but not LNCaP cells. However, knockdown of miR-296-Sp inhibited the growth rate of LNCaP cells cultured in absence of androgen. Conclusion MiR-296-5p could be irnportant for development of prostate cancer from androgen dependence to androgen independence.

  18. Androgen-independent proliferation of LNCaP prostate cancer cells infected by xenotropic murine leukemia virus-related virus

    International Nuclear Information System (INIS)

    Highlights: • XMRV infection induces androgen-independent growth in LNCaP cells. • XMRV infection reduces expression of androgen receptor. • XMRV promotes appearance of androgen blocker-resistant prostate cancer cells. - Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a novel gammaretrovirus that was originally isolated from human prostate cancer. It is now believed that XMRV is not the etiologic agent of prostate cancer. An analysis of murine leukemia virus (MLV) infection in various human cell lines revealed that prostate cancer cell lines are preferentially infected by XMRV, and this suggested that XMRV infection may confer some sort of growth advantage to prostate cancer cell lines. To examine this hypothesis, androgen-dependent LNCaP cells were infected with XMRV and tested for changes in certain cell growth properties. We found that XMRV-infected LNCaP cells can proliferate in the absence of the androgen dihydrotestosterone. Moreover, androgen receptor expression is significantly reduced in XMRV-infected LNCaP cells. Such alterations were not observed in uninfected and amphotropic MLV-infected LNCaP cells. This finding explains why prostate cancer cell lines are preferentially infected with XMRV

  19. Androgen-independent proliferation of LNCaP prostate cancer cells infected by xenotropic murine leukemia virus-related virus

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    Kakoki, Katsura [Division of Cytokine Signaling, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki 852-8523 (Japan); Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kamiyama, Haruka [Division of Cytokine Signaling, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki 852-8523 (Japan); Izumida, Mai; Yashima, Yuka; Hayashi, Hideki [Division of Cytokine Signaling, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Yamamoto, Naoki [Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki 852-8523 (Japan); Department of Microbiology, National University of Singapore (Singapore); Matsuyama, Toshifumi [Division of Cytokine Signaling, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Igawa, Tsukasa; Sakai, Hideki [Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kubo, Yoshinao, E-mail: yoshinao@nagasaki-u.ac.jp [Division of Cytokine Signaling, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Department of AIDS Research, Institute of Tropical Medicine, G-COE, Nagasaki University, Nagasaki 852-8523 (Japan)

    2014-04-25

    Highlights: • XMRV infection induces androgen-independent growth in LNCaP cells. • XMRV infection reduces expression of androgen receptor. • XMRV promotes appearance of androgen blocker-resistant prostate cancer cells. - Abstract: Xenotropic murine leukemia virus-related virus (XMRV) is a novel gammaretrovirus that was originally isolated from human prostate cancer. It is now believed that XMRV is not the etiologic agent of prostate cancer. An analysis of murine leukemia virus (MLV) infection in various human cell lines revealed that prostate cancer cell lines are preferentially infected by XMRV, and this suggested that XMRV infection may confer some sort of growth advantage to prostate cancer cell lines. To examine this hypothesis, androgen-dependent LNCaP cells were infected with XMRV and tested for changes in certain cell growth properties. We found that XMRV-infected LNCaP cells can proliferate in the absence of the androgen dihydrotestosterone. Moreover, androgen receptor expression is significantly reduced in XMRV-infected LNCaP cells. Such alterations were not observed in uninfected and amphotropic MLV-infected LNCaP cells. This finding explains why prostate cancer cell lines are preferentially infected with XMRV.

  20. Phosphoproteome analysis demonstrates the potential role of THRAP3 phosphorylation in androgen-independent prostate cancer cell growth.

    Science.gov (United States)

    Ino, Yoko; Arakawa, Noriaki; Ishiguro, Hitoshi; Uemura, Hiroji; Kubota, Yoshinobu; Hirano, Hisashi; Toda, Tosifusa

    2016-04-01

    Elucidating the androgen-independent growth mechanism is critical for developing effective treatment strategies to combat androgen-independent prostate cancer. We performed a comparative phosphoproteome analysis using a prostate cancer cell line, LNCaP, and an LNCaP-derived androgen-independent cell line, LNCaP-AI, to identify phosphoproteins involved in this mechanism. We performed quantitative comparisons of the phosphopeptide levels in tryptic digests of protein extracts from these cell lines using MS. We found that the levels of 69 phosphopeptides in 66 proteins significantly differed between LNCaP and LNCaP-AI. In particular, we focused on thyroid hormone receptor associated protein 3 (THRAP3), which is a known transcriptional coactivator of the androgen receptor. The phosphorylation level of THRAP3 was significantly lower at S248 and S253 in LNCaP-AI cells. Furthermore, pull-down assays showed that 32 proteins uniquely bound to the nonphosphorylatable mutant form of THRAP3, whereas 31 other proteins uniquely bound to the phosphorylation-mimic form. Many of the differentially interacting proteins were identified as being involved with RNA splicing and processing. These results suggest that the phosphorylation state of THRAP3 at S248 and S253 might be involved in the mechanism of androgen-independent prostate cancer cell growth by changing the interaction partners.

  1. Differential Effects of Leptin on the Invasive Potential of Androgen-Dependent and -Independent Prostate Carcinoma Cells

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    Dayanand D. Deo

    2008-01-01

    Full Text Available Obesity has been linked with an increased risk of prostate cancer. The formation of toxic free oxygen radicals has been implicated in obesity mediated disease processes. Leptin is one of the major cytokines produced by adipocytes and controls body weight homeostasis through food intake and energy expenditure. The rationale of the study was to determine the impact of leptin on the metastatic potential of androgen-sensitive (LNCaP cells as well as androgen-insensitive (PC-3 and DU-145 cells. At a concentration of 200_nm, LNCaP cells showed a significant increase (20% above control; P<.0001 in cellular proliferation without any effect on androgen-insensitive cells. Furthermore, exposure to leptin caused a significant (P<.01 to P<.0001 dose-dependent decrease in migration and invasion of PC3 and Du-145 prostate carcinoma cell lines. At the molecular level, exposure of androgen-independent prostate cancer cells to leptin stimulates the phosphorylation of MAPK at early time point as well as the transcription factor STAT3, suggesting the activation of the intracellular signaling cascade upon leptin binding to its cognate receptor. Taken together, these results suggest that leptin mediates the invasive potential of prostate carcinoma cells, and that this effect is dependent on their androgen sensitivity.

  2. Prolonged androgen deprivation leads to downregulation of androgen receptor and prostate-specific membrane antigen in prostate cancer cells

    OpenAIRE

    Liu, Tiancheng; Wu, Lisa Y.; Fulton, Melody D.; JOHNSON, JACQUELINE M.; Berkman, Clifford E.

    2012-01-01

    Emergence of androgen-independent cancer cells during androgen deprivation therapy presents a significant challenge to successful treatment outcomes in prostate cancer. Elucidating the role of androgen deprivation in the transition from an androgen-dependent to an androgen-independent state may enable the development of more effective therapeutic strategies against prostate cancer. Herein, we describe an in vitro model for assessing the effects of continuous androgen-deprivation on prostate c...

  3. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    International Nuclear Information System (INIS)

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  4. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

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    Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

    2013-11-15

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  5. Loss of androgen receptor-dependent growth suppression by prostate cancer cells can occur independently from acquiring oncogenic addiction to androgen receptor signaling.

    Directory of Open Access Journals (Sweden)

    Jason M D'Antonio

    Full Text Available The conversion of androgen receptor (AR signaling as a mechanism of growth suppression of normal prostate epithelial cells to that of growth stimulation in prostate cancer cells is often associated with AR mutation, amplification and over-expression. Thus, down-regulation of AR signaling is commonly therapeutic for prostate cancer. The E006AA cell line was established from a hormone naïve, localized prostate cancer. E006AA cells are genetically aneuploid and grow equally well when xenografted into either intact or castrated male NOG but not nude mice. These cells exhibit: 1 X chromosome duplication and AR gene amplification, although paradoxically not coupled with increased AR expression, and 2 somatic, dominant-negative Serine-599-Glycine loss-of-function mutation within the dimerization surface of the DNA binding domain of the AR gene. No effect on the growth of E006AA cells is observed using targeted knockdown of endogenous mutant AR, ectopic expression of wild-type AR, or treatment with androgens or anti-androgens. E006AA cells represent a prototype for a newly identified subtype of prostate cancer cells that exhibit a dominant-negative AR loss-of-function in a hormonally naïve patient. Such loss-of-function eliminates AR-mediated growth suppression normally induced by normal physiological levels of androgens, thus producing a selective growth advantage for these malignant cells in hormonally naïve patients. These data highlight that loss of AR-mediated growth suppression is an independent process, and that, without additional changes, is insufficient for acquiring oncogene addiction to AR signaling. Thus, patients with prostate cancer cells harboring such AR loss-of-function mutations will not benefit from aggressive hormone or anti-AR therapies even though they express AR protein.

  6. Histological changes caused by meclofenamic acid in androgen independent prostate cancer tumors: evaluation in a mouse model

    Directory of Open Access Journals (Sweden)

    Iván Delgado-Enciso

    2015-10-01

    Full Text Available ABSTRACT Meclofenamic acid is a nonsteroidal anti-inflammatory drug that has shown therapeutic potential for different types of cancers, including androgen-independent prostate neoplasms. The antitumor effect of diverse nonsteroidal anti-inflammatory drugs has been shown to be accompanied by histological and molecular changes that are responsible for this beneficial effect. The objective of the present work was to analyze the histological changes caused by meclofenamic acid in androgen-independent prostate cancer. Tumors were created in a nude mouse model using PC3 cancerous human cells. Meclofenamic acid (10 mg/kg/day; experimental group, n=5 or saline solution (control group, n=5 was administered intraperitoneally for twenty days. Histological analysis was then carried out on the tumors, describing changes in the cellular architecture, fibrosis, and quantification of cellular proliferation and tumor vasculature. Meclofenamic acid causes histological changes that indicate less tumor aggression (less hypercellularity, fewer atypical mitoses, and fewer nuclear polymorphisms, an increase in fibrosis, and reduced cellular proliferation and tumor vascularity. Further studies are needed to evaluate the molecular changes that cause the beneficial and therapeutic effects of meclofenamic acid in androgen-independent prostate cancer.

  7. Inhibition of Androgen-Independent Prostate Cancer by Estrogenic Compounds Is Associated with Increased Expression of Immune-Related Genes

    Directory of Open Access Journals (Sweden)

    Ilsa M. Coleman

    2006-10-01

    Full Text Available The clinical utility of estrogens for treating prostate cancer (CaP was established in the 1940s by Huggins. The classic model of the anti-CaP activity of estrogens postulates an indirect mechanism involving the suppression of androgen production. However, clinical, preclinical studies have shown that estrogens exert growth-inhibitory effects on CaP under low-androgen conditions, suggesting additional modes whereby estrogens affect CaP cells and/or the microenvironment. Here we have investigated the activity of 17β estradiol (E2 against androgen-independent CaP, identified molecular alterations in tumors exposed to E2. E2 treatment inhibited the growth of all four androgen-independent CaP xenografts studied (LuCaP 35V, LuCaP 23.1AI, LuCaP 49, LuCaP 58 in castrated male mice. The molecular basis of growth suppression was studied by cDNA microarray analysis, which indicated that multiple pathways are altered by E2 treatment. Of particular interest are changes in transcripts encoding proteins that mediate immune responses, regulate androgen receptor signaling. In conclusion, our data show that estrogens have powerful inhibitory effects on CaP in vivo in androgendepleted environments, suggest novel mechanisms of estrogen-mediated antitumor activity. These results indicate that incorporating estrogens into CaP treatment protocols could enhance therapeutic efficacy even in cases of advanced disease.

  8. Mitochondrial DNA determines androgen dependence in prostate cancer cell lines

    OpenAIRE

    Higuchi, M; Kudo, T; Suzuki, S.; Evans, TT; Sasaki, R.; Wada, Y; Shirakawa, T.; Sawyer, JR; Gotoh, A

    2006-01-01

    Prostate cancer progresses from an androgen-dependent to androgen-independent stage after androgen ablation therapy. Mitochondrial DNA plays a role in cell death and metastatic competence. Further, heteroplasmic large-deletion mitochondrial DNA is verycommon in prostate cancer. To investigate the role of mitochondrial DNA in androgen dependence of prostate cancers, we tested the changes of normal and deleted mitochondrial DNA in accordance with the progression of prostate cancer. We demonstra...

  9. Metabolic action of prolactin in regressing prostate: independent of androgen action

    International Nuclear Information System (INIS)

    The mechanism of the observed synergistic effect of prolactin and androgen on the lateral lobe of the rat prostate is not established. The observation that prolactin alone delayed the rate of loss of weight, protein, and DNA of the lateral lobe in castrated rats has led us to question the assumption that the effect of prolactin is produced by a modification of recognized androgen-induced intracellular changes. The present study was conducted to explore whether or not the sites of prolactin action in the rat prostate coincided with those recognized as the androgen effect. Two anterior pituitaries from female donors were grafted under the right renal capsule of adult male Sprague-Dawley rats. Seven days later, bilateral orchiectomy and unilateral nephrectomy were performed in these rats. In one half of the animals, the kidney bearing the pituitary grafts was removed. In the other half, the contralateral kidney was removed. Seven days following the orchiectomy-nephrectomy, animals bearing the pituitary grafts had a higher level of serum prolactin (93 +/- 7 ng/ml, mean +/- SE) than in those without the graft (26 +/- 3 ng/ml). This condition of hyperprolactinemia was associated with the delay of castration-induced regression in the lateral prostate. The rate of protein degradation, as judged by the amount of radioactivity remaining in the tissue following a single i.v. pulse of 3H-leucine 24 hr before orchiectomy-nephrectomy, was significantly slower in the lateral prostate in graft-bearing animals than in those without grafts

  10. Metabolic action of prolactin in regressing prostate: independent of androgen action

    Energy Technology Data Exchange (ETDEWEB)

    Smith, C.; Assimos, D.; Lee, C.; Grayhack, J.T.

    1985-01-01

    The mechanism of the observed synergistic effect of prolactin and androgen on the lateral lobe of the rat prostate is not established. The observation that prolactin alone delayed the rate of loss of weight, protein, and DNA of the lateral lobe in castrated rats has led us to question the assumption that the effect of prolactin is produced by a modification of recognized androgen-induced intracellular changes. The present study was conducted to explore whether or not the sites of prolactin action in the rat prostate coincided with those recognized as the androgen effect. Two anterior pituitaries from female donors were grafted under the right renal capsule of adult male Sprague-Dawley rats. Seven days later, bilateral orchiectomy and unilateral nephrectomy were performed in these rats. In one half of the animals, the kidney bearing the pituitary grafts was removed. In the other half, the contralateral kidney was removed. Seven days following the orchiectomy-nephrectomy, animals bearing the pituitary grafts had a higher level of serum prolactin (93 +/- 7 ng/ml, mean +/- SE) than in those without the graft (26 +/- 3 ng/ml). This condition of hyperprolactinemia was associated with the delay of castration-induced regression in the lateral prostate. The rate of protein degradation, as judged by the amount of radioactivity remaining in the tissue following a single i.v. pulse of /sup 3/H-leucine 24 hr before orchiectomy-nephrectomy, was significantly slower in the lateral prostate in graft-bearing animals than in those without grafts.

  11. Prostate-Specific Antigen Nadir and Time to Prostate-Specific Antigen Nadir Following Maximal Androgen Blockade Independently Predict Prognosis in Patients with Metastatic Prostate Cancer

    OpenAIRE

    Hong, Seok Young; Cho, Dae Sung; Kim, Sun Il; Ahn, Hyun Soo; Kim, Se Joong

    2012-01-01

    Purpose To evaluate the influence of prostate-specific antigen (PSA) kinetics following maximal androgen blockade (MAB) on disease progression and cancer-specific survival in patients with metastatic, hormone-sensitive prostate cancer. Materials and Methods One hundred thirty-one patients with metastatic, hormone-sensitive prostate cancer treated with MAB at our institution were included in this study. Patients' characteristics, PSA at MAB initiation, PSA nadir, time to PSA nadir (TTN), and P...

  12. Androgen and prostatic stroma

    Institute of Scientific and Technical Information of China (English)

    Yuan-JieNIU; Teng-XiangMA; IuZHANG; YongXU; Rui-FaHAN; GuangSUN

    2003-01-01

    Aim:To investigate the effect of androgen on the proliferation,differentiation and regression of canine prostatic stromal cells in vivo and human stromal cells in vitro.Methods:Twenty-two dogs,including 15 normal prostate doge and 7 prostatic hyperplasia dogs,had their serum concentration of testosterone and estrodiol determined by radioimmunoassay before and after castration.The expression of androgen receptor(AR)and estrogen receptor(ER)in the prostate were analysed by immunohistochemistry and semi-quantitative RT-PCR before and after castration.Light microscopy,transmission electron microscopy and TUNEL assay were carried out successively before and after castration to evaluate the prostatic histomorphology.In vitro serum-free cell cultures from human prostatic stroma were established and exposed to dihydrotestosterone(DHT).The proliferation of the cell culture was detected by MTT assay.The expression of TGFβ bFGF,AR,and smooth muscle cell(SMC) specific proteins (myosin and/or smoothelin)were detected using immunohistochemistry and RT-PCR.The differentiation from fibroblasts to smooth muscle cells was deduced by measuring the expression of SMC specific proteins.Results:Before castration,the serum concentrations of testosterone and estrodiol were not statistically different between normal and hyperplasia groups.Following castration,the serum concentration of testerone decreased rapidly in 2 days,and the concentration of estrodiol had no significant change compared with the pre-castration data.In the prostate,AR was presented in both the epithelial and stromal cells and the AR mRNA level was higher in hyperplasia than in normal prostate tissues(P<0.05).While ER predominantly existed in the prostate stromal cells and the ER mRNA had no difference between the hyperplasia and the normal group.Within the early phase of castration(

  13. Androgen and taxol cause cell type-specific alterations of centrosome and DNA organization in androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cells

    Science.gov (United States)

    Schatten, H.; Ripple, M.; Balczon, R.; Weindruch, R.; Chakrabarti, A.; Taylor, M.; Hueser, C. N.

    2000-01-01

    We investigated the effects of androgen and taxol on the androgen-responsive LNCaP and androgen-independent DU145 prostate cancer cell lines. Cells were treated for 48 and 72 h with 0.05-1 nM of the synthetic androgen R1881 and with 100 nM taxol. Treatment of LNCaP cells with 0.05 nM R1881 led to increased cell proliferation, whereas treatment with 1 nM R1881 resulted in inhibited cell division, DNA cycle arrest, and altered centrosome organization. After treatment with 1 nM R1881, chromatin became clustered, nuclear envelopes convoluted, and mitochondria accumulated around the nucleus. Immunofluorescence microscopy with antibodies to centrosomes showed altered centrosome structure. Although centrosomes were closely associated with the nucleus in untreated cells, they dispersed into the cytoplasm after treatment with 1 nM R1881. Microtubules were only faintly detected in 1 nM R1881-treated LNCaP cells. The effects of taxol included microtubule bundling and altered mitochondria morphology, but not DNA organization. As expected, the androgen-independent prostate cancer cell line DU145 was not affected by R1881. Treatment with taxol resulted in bundling of microtubules in both cell lines. Additional taxol effects were seen in DU145 cells with micronucleation of DNA, an indication of apoptosis. Simultaneous treatment with R1881 and taxol had no additional effects on LNCaP or DU145 cells. These results suggest that LNCaP and DU145 prostate cancer cells show differences not only in androgen responsiveness but in sensitivity to taxol as well. Copyright 2000 Wiley-Liss, Inc.

  14. The androgen receptor: Functional structure and expression in transplanted human prostate tumors and prostate tumor cell lines

    OpenAIRE

    Trapman, Jan; Ris-Stalpers, Carolyn; Korput, J. A G M; Kuiper, George; Faber, P.W.; Romijn, Johannes; Mulder, Eppo; Brinkmann, Albert

    1990-01-01

    markdownabstractAbstract The growth of the majority of prostate tumors is androgen-dependent, for which the presence of a functional androgen receptor is a prerequisite. Tumor growth can be inhibited by blockade of androgen receptor action. However, this inhibition is transient. To study the role of the androgen receptor in androgen-dependent and androgen-independent prostate tumor cell growth, androgen receptor mRNA expression was monitored in six different human prostate tumor cell lines an...

  15. Expression changes of androgen receptor RNA in androgen-independence prostatic cancer%前列腺癌雄激素依赖转化后雄激素受体基因表达变化的研究

    Institute of Scientific and Technical Information of China (English)

    潘寿华; 阎家峻; 郑专

    2011-01-01

    Background and purpose: The mechanism for transforming androgen-dependent prostatic cancer cells into androgen-independent prostatic cancer cells is uncertain. Androgen receptor RNA plays a vital role in transforming androgen-dependent prostatic cancer into androgen-independent prostatic cancer. This study investigated the transcription of androgen receptor (AR) RNA in order to determine the role of AR-RNA in the transformation.Methods: Thirty three patients with prostate cancer were treated using androgen deprivation and all of the patients had long time follow-up. Of these patients, 18 were transformed into the androgen-independent prostatic cancer. The transcription of AR RNA was detected using RT-PCR at androgen-dependent and androgen-independent conditions in 18 patients, and before or after androgen deprivation in 15 patients. Results: The transcription of androgen receptor RNA at androgen-dependent and androgen-independent conditions in 18 patients were [(28.4±3.4) Ct vs (36.7±1.8) Ct, t=14.43, P<0.001]. Before and after androgen deprivation in 15 patients were [(29.5±3.1) Ct vs (29.1±3.2) Ct,t=0.409, P>0.05]. Conclusion: The elevation of transcription in androgen receptor RNA is most likely related to the mechanism used for the transformation of androgen-dependent prostatic cancer into androgen-independent prostatic cancer.%背景与目的:前列腺癌雄激素依赖性转化的机制目前尚不完全清楚,多数认为雄激素受体(androgen receptor,AR)基因的变化可能起重要作用,本研究主要探讨AR基因表达变化在前列腺癌雄激素依赖转化过程中的作用.方法:通过对33例晚期前列腺癌患者进行雄激素阻断治疗并长时间的随访,期间有18例患者发生了雄激素依赖转化,15例患者未发生雄激素依赖转化.采用RT-PCR法测定18例患者雄激素依赖转化前后及15例患者雄激素阻断治疗前后癌细胞内AR基因的表达情况.结果:18例患者雄激素依赖转化前

  16. Clinical evaluation of internal iliac artery anticancer drug infusion for the treatment of androgen-independent prostate cancer

    International Nuclear Information System (INIS)

    Objective: To evaluate the clinical efficacy of bilateral internal iliac artery chemotherapy infusion for the treatment of androgen-independent prostate cancer (ALPC). Methods: Thirty eight eases of confirmed AIPC were randomly divided into treatment group and control group. The patients in treatment group (23 cases) were treated with androgen deprivation therapy and regular internal iliac artery chemotherapy, while patients in control group (15 cases) were only received androgen deprivation therapy. The therapeutic efficacies of the two groups were compared and analyzed after completion of the treatment. Results: The clinical symptoms and maximum urine flow rates of' treatment group were improved rapidly 6 months later. After 2 years follow-up, the total efficacies of treatment group and control group were 65.2% and 26.7% respectively, showing a significant statistical difference (P<0.05). Conclusions: The treatment of AlPC with bilateral internal iliac artery chemotherapy is effective, providing melioration the quality of life and alleviation of the symptoms. (authors)

  17. Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and epiregulin in androgen-independent prostate cancer cell lines.

    DEFF Research Database (Denmark)

    Tørring, Niels; Sørensen, Boe Sandahl; Nexø, Ebba

    2000-01-01

    BACKGROUND: The proliferation of androgen-independent prostate cancer cell lines has previously been shown to be influenced by an autocrine loop of the epidermal growth factor (EGF) system. This observation has alerted us to study the expression of ligands and receptors from the EGF-system in pro...

  18. p38MAPK activation is involved in androgen-independent proliferation of human prostate cancer cells by regulating IL-6 secretion

    International Nuclear Information System (INIS)

    Increased levels of serum interleukin-6 (IL-6) are frequently observed in patients with advanced, hormone-refractory prostate cancer. However, the precise mechanism of IL-6 regulation is still largely unknown. Since prostate cancer gradually progresses to an androgen-independent state despite the stress caused by various therapeutic agents, we hypothesized the stress-activated protein kinases (SAPKs) involvement in androgen-independent growth or IL-6 secretion of prostate cancer cells. Using PC-3 and DU145 human prostate cancer cells, we analyzed the role of SAPKs in IL-6 mediated cell growth and found that the p38MAPK and JNK are involved in androgen-independent cancer cell growth. Furthermore, IL-6 secretion by PC-3 and DU145 cells was significantly suppressed by SAPKs inhibitor, especially by p38MAPK inhibitor SB203580, but not by JNK inhibitor SP600125 nor by MEK inhibitor, PD98059. These results raised the possibility that the IL-6 mediated androgen-independent proliferation of PC-3 and DU145 cells is regulated at least partly via SAPKs signaling pathway especially through p38MAPK activation

  19. Rapamycin enhances the susceptibility of both androgen-dependent and-independent prostate carcinoma cells to docetaxel

    Institute of Scientific and Technical Information of China (English)

    LIU Qing-jun; XU Xiu-hong; SHANG Dong-hao; TIAN Ye; L(U) Wen-cheng; ZHANG Yu-hai

    2010-01-01

    Background Docetaxel (DOC) therapy is well tolerated and shows high response rates in patients with hormone refractory prostate cancer (HRPC). There are many reports on the effect of rapamycin (RPM) on the treatment of carcinogenesis. The goal of this study was to test whether RPM could enhance the susceptibility of both androgen-dependent and -independent prostate carcinoma cells to DOC.Methods Prostate cancer (PC) cell lines (LNCap, PC3 and AILNCap) were cultured and treated with RPM and DOC alone or in combination. The effects of therapeutic agents on cells were determined by the WST-1 assay. Apoptosis induction was confirmed by flow cytometric analysis. The apopcyto caspase colorimetric assay kit was applied to measure the activities of caspases 3 and 9. The antitumor effects of RPM and DOC against PC cells were also assessed in nude mice using four randomized groups: control, RPM, DOC and combination drug therapy by measuring tumor size. All the animals tolerated both RPM and DOC without significant weight loss.Results RPM and DOC caused dosage-dependent growth suppression of PC cells. RPM could increase the susceptibility of PC cells to DOC significantly, and combined treatment with RPM and DOC caused synergistic growth suppression in all examined PC cell lines by isobolographic analysis. Both RPM and DOC significantly induced apoptosis in a dosage-dependent manner. RPM (10 nmol/L), DOC (1 nmol/L), and combined treatment induced apoptosis rate were 8%, 17% and 38%, respectively (the control was 2%). RPM could promote the apoptosis induced by DOC in PC cell lines. Both RPM and DOC significantly increased the caspase activity in a dosage-dependent manner. The relative activities of caspase 9 in control, RPM, DOC and RPM+DOC groups were 0.22±0.02, 0.36±0.06, 0.47±0.05 and 0.84±0.08, respectively. The relative activities of cespase 3 were 0.21±0.02, 0.24±0.05, 0.42±0.06 and 0.81±0.09, respectively. Either RPM or DOC alone significantly inhibited the

  20. Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer.

    Science.gov (United States)

    Narizhneva, Natalia V; Tararova, Natalia D; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G; Purmal, Andrei A; Gudkov, Andrei V; Gurova, Katerina V

    2009-12-15

    In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization.

  1. Role of androgen receptor in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    HiroyoshiSuzuki; HaruoIto

    1999-01-01

    The growth of prostate cancer is sensitive to androgen, and hormonal therapy has been used for treatment of ad-vanced cancer. About 80 % of prostate cancers initially respond to hormonal therapy, howcrver, more than half of the re-sponders gradtmlly become resistant to this therapy. Changes in tumors from an androgen-responsive to an androgen-unre-sponsive state have been widely discussed. Since androgen action is mediated by androgen receptor (AR), abnonnalitiesof AR is believed to play an important role of the loss of androgen responsiveness in prostate cancer. "Ilais article focusedon the role of AR in the progression of prostate cancer.

  2. A Mathematical Model of Intermittent Androgen Suppression for Prostate Cancer

    Science.gov (United States)

    Ideta, Aiko Miyamura; Tanaka, Gouhei; Takeuchi, Takumi; Aihara, Kazuyuki

    2008-12-01

    For several decades, androgen suppression has been the principal modality for treatment of advanced prostate cancer. Although the androgen deprivation is initially effective, most patients experience a relapse within several years due to the proliferation of so-called androgen-independent tumor cells. Bruchovsky et al. suggested in animal models that intermittent androgen suppression (IAS) can prolong the time to relapse when compared with continuous androgen suppression (CAS). Therefore, IAS has been expected to enhance clinical efficacy in conjunction with reduction in adverse effects and improvement in quality of life of patients during off-treatment periods. This paper presents a mathematical model that describes the growth of a prostate tumor under IAS therapy based on monitoring of the serum prostate-specific antigen (PSA). By treating the cancer tumor as a mixed assembly of androgen-dependent and androgen-independent cells, we investigate the difference between CAS and IAS with respect to factors affecting an androgen-independent relapse. Numerical and bifurcation analyses show how the tumor growth and the relapse time are influenced by the net growth rate of the androgen-independent cells, a protocol of the IAS therapy, and the mutation rate from androgen-dependent cells to androgen-independent ones.

  3. Primary Research on Chinese Medicine Treatment of Androgen-Independent Prostate Cancer

    Institute of Scientific and Technical Information of China (English)

    张蜀武; 周仕轶; 邵继春; 曲晓伟

    2009-01-01

    Prostate cancer(PC) is a common malignant tumor in the male seniors,and its incidence has been ascending in China in recent years. Over 80%of the patients are diagnosed as being in the late stage and lose the opportunity of radical operation because of its early stage metastasis. Endocrinotherapy is regarded

  4. Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.

    Directory of Open Access Journals (Sweden)

    Yao Dai

    Full Text Available Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins.We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1, with IC₅₀ in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues.Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be

  5. Detection of bony metastases of androgen-independent prostate cancer by PET-FDG

    Energy Technology Data Exchange (ETDEWEB)

    Yeh, Samuel D. J.; Imbriaco, Massimo; Larson, Steven M.; Garza, Dahlia; Zhang Jiaju; Kalaigian, Hovanes; Finn, Ronald D.; Reddy, David; Horowitz, Steven M.; Goldsmith, Stanley J.; Scher, Howard I

    1996-08-01

    Fourteen F-18 fluorodeoxyglucose (FDG) studies were carried out in 13 patients known to have bony metastases from carcinoma of the prostate. One patient was newly diagnosed. The remaining patients had various types of therapy and were considered hormonally resistant. The average age was 67. All patients had extensive bony metastases shown on the conventional Tc99m-MDP bone scans. Only about 18% of bony lesions apparent on the conventional bone scans showed corresponding increase of FDG uptake. Anatomical correlation was performed by using co-registered images of SPECT and PET in the same area. The positive FDG uptake was not related to the duration of illness, level of PSA, previous therapy, and magnitude of disease involvement. It appears that only a small percentage of bony metastases is associated with increased glycolysis. It is possible that other metabolic processes are more important than glycolysis for providing prostate cancer with a source of energy and nutrients.

  6. Androgen receptor signaling is required for androgen-sensitive human prostate cancer cell proliferation and survival

    Directory of Open Access Journals (Sweden)

    Day Wanda V

    2005-04-01

    Full Text Available Abstract Background Androgens and androgen receptors (AR regulate normal prostate development and growth. They also are involved in pathological development of prostatic diseases, including benign prostatic hyperplasia (BPH and prostate cancer (PCa. Antiandrogen therapy for PCa, in conjunction with chemical or surgical castration, offers initial positive responses and leads to massive prostate cell death. However, cancer cells later appear as androgen-independent PCa. To investigate the role of AR in prostate cell proliferation and survival, we introduced a vector-based small interfering RNA (siRNA. This siRNA targeted 5'-untranslated region of AR mRNA for extended suppression of AR expression in androgen-sensitive human prostate LNCaP cells. Results The siRNA design successfully suppressed endogenous AR expression, as revealed by western blotting and immunofluorescence staining in LNCaP cells. LNCaP cells did not proliferate in the absence of AR and underwent apoptosis, based on elevated phospho-Histone H2B expression and higher number of apoptotic body as compared to control cells. Conclusion We demonstrated that AR is vital for prostate cell proliferation and survival in this androgen-sensitive prostate cell line. These results further strengthen the hypothesis that AR can be a therapeutic target for treating androgen-sensitive stages of PCa. Unlike antiandorgens, however, siRNA targeting AR provides a direct inactivation of AR function through the suppression of AR protein expression.

  7. Androgen Control in Prostate Cancer.

    Science.gov (United States)

    Pelekanou, Vasiliki; Castanas, Elias

    2016-10-01

    Research on prostate cancer has extensively advanced in the past decade, through an improved understanding for its genetic basis and risk-stratification. Molecular classification of prostate cancer into distinct subtypes and the recognition of new histologic entities promise the development of tailored-made management strategies of patients. Nowadays, various alternatives are available for clinical management of localized disease ranging from observation alone through radical prostatectomy. In patients with castration-resistant prostate cancer, the approval of new drugs for the management of metastatic disease has offered promising results improving the survival of these patients. In this context, androgen receptors (AR) remain at the epicenter of prostate cancer research holding a prominent role in the biology and therapeutic regimens of prostate cancer. As many of castration-resistant tumors retain hormone-responsiveness, AR is a clinical relevant, druggable target. However, AR paradoxically remains neglected as a prostate cancer biomarker. The great advancements in prostate cancer preclinical and clinical research, imply further improvement in clinical and translational data, for patient selection and treatment optimization. For a precision medicine-guided clinical management of prostate cancer, AR evaluation has to be implemented in companion and complementary diagnostics, as discussed here. J. Cell. Biochem. 117: 2224-2234, 2016. © 2016 Wiley Periodicals, Inc. PMID:27104784

  8. PSA Response to Neoadjuvant Androgen Deprivation Therapy Is a Strong Independent Predictor of Survival in High-Risk Prostate Cancer in the Dose-Escalated Radiation Therapy Era

    Energy Technology Data Exchange (ETDEWEB)

    McGuire, Sean E., E-mail: semcguir@mdanderson.org [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (United States); Lee, Andrew K. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Cerne, Jasmina Z. [Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas (United States); Munsell, Mark F. [Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Levy, Lawrence B. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kudchadker, Rajat J. [Department of Radiation Physics, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Choi, Seungtaek L.; Nguyen, Quynh N.; Hoffman, Karen E.; Pugh, Thomas J.; Frank, Steven J. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Corn, Paul G.; Logothetis, Christopher J. [Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Kuban, Deborah A. [Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-01-01

    Purpose: The aim of the study was to evaluate the prognostic value of prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. Methods and Materials: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long-term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specific mortality (PCSM) and overall survival (OS) were examined. Results: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs {>=}0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. Conclusions: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level {>=}0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level {>=}0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation.

  9. Withaferin A Induces Cell Death Selectively in Androgen-Independent Prostate Cancer Cells but Not in Normal Fibroblast Cells.

    Directory of Open Access Journals (Sweden)

    Yukihiro Nishikawa

    Full Text Available Withaferin A (WA, a major bioactive component of the Indian herb Withania somnifera, induces cell death (apoptosis/necrosis in multiple types of tumor cells, but the molecular mechanism underlying this cytotoxicity remains elusive. We report here that 2 μM WA induced cell death selectively in androgen-insensitive PC-3 and DU-145 prostate adenocarcinoma cells, whereas its toxicity was less severe in androgen-sensitive LNCaP prostate adenocarcinoma cells and normal human fibroblasts (TIG-1 and KD. WA also killed PC-3 cells in spheroid-forming medium. DNA microarray analysis revealed that WA significantly increased mRNA levels of c-Fos and 11 heat-shock proteins (HSPs in PC-3 and DU-145, but not in LNCaP and TIG-1. Western analysis revealed increased expression of c-Fos and reduced expression of the anti-apoptotic protein c-FLIP(L. Expression of HSPs such as HSPA6 and Hsp70 was conspicuously elevated; however, because siRNA-mediated depletion of HSF-1, an HSP-inducing transcription factor, reduced PC-3 cell viability, it is likely that these heat-shock genes were involved in protecting against cell death. Moreover, WA induced generation of reactive oxygen species (ROS in PC-3 and DU-145, but not in normal fibroblasts. Immunocytochemistry and immuno-electron microscopy revealed that WA disrupted the vimentin cytoskeleton, possibly inducing the ROS generation, c-Fos expression and c-FLIP(L suppression. These observations suggest that multiple events followed by disruption of the vimentin cytoskeleton play pivotal roles in WA-mediated cell death.

  10. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation

    OpenAIRE

    Mahajan, Nupam P.; Liu, Yuanbo; Majumder, Samarpan; Warren, Maria R.; Parker, Carol E.; Mohler, James L.; Earp, H. Shelton; Whang, Young E.

    2007-01-01

    Activation of the androgen receptor (AR) may play a role in androgen-independent progression of prostate cancer. Multiple mechanisms of AR activation, including stimulation by tyrosine kinases, have been postulated. We and others have recently shown involvement of activated Cdc42-associated tyrosine kinase Ack1 in advanced human prostate cancer. Here we provide the molecular basis for interplay between Ack1 and AR in prostate cancer cells. Activated Ack1 promoted androgen-independent growth o...

  11. Pomegranate Polyphenols Downregulate Expression of Androgen Synthesizing Genes in Human Prostate Cancer Cells Overexpressing the Androgen Receptor

    OpenAIRE

    Hong, Mee Young; Seeram, Navindra P.; Heber, David

    2008-01-01

    Prostate cancer is dependent on circulating testosterone in its early stages and is treatable with radiation and surgery. However, recurrent prostate tumors advance to an androgen-independent state where they progress in the absence of circulating testosterone leading to metastasis and death. During the development of androgen independence, prostate cancer cells are known to increase intracellular testosterone synthesis which maintains cancer cell growth in the absence of significant amounts ...

  12. Contragestazol (DL111-IT) inhibits proliferation of human androgen-independent prostate cancer cell line PC3 in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    Qiao-Jun He; Bo Yang; Yi-Jia Lou; Rui-Ying Fang

    2005-01-01

    Aim: To evaluate the antiproliferative activity of contragestazol (DL 1 11-IT) on the human prostate cancer cell line PC3 in vitro and in vivo and to elucidate its potential molecular mechanisms. Methods: The cell killing ability of DL111-IT was measured by the 3-(4,5-dimethylthia-zol,2-yl)-2,5-diphenyltetrazolium bromide (MTT) reagent assay method and the tumor xenograft model. The cell cycle was analyzed by flow cytometry and protein expression,including retinoblastoma (pRb), cyclin-dependent kinase 4 (CDK4) and cyclin D1, was detected by Western blotting.Results: DL111-IT exhibited high efficiency on cell growth inhibition of the human androgen-independent prostate cancer cell line PC3. The drug concentration that yielded 50 % cell inhibition (IC50 value) was 9.9 mg/mL. In the PC3tumor xenograft study, DL111-IT (1.25 mg/kg-20.0 mg/kg) given once a day for 10 days significantly inhibited tumor growth, with the inhibition rate ranging from 21% to 50 %. Flow cytometric analysis indicated that DL111-IT could cause G1 arrest in the PC3 cell line, but not apoptosis. DL111-IT enhanced pRb expression and down-regulated CDK4and cyclin D1 expression, suggesting that cell cycle regulation might contribute to the anticancer property of DL111-IT. Conclusion: DL111-Itinhibits the proliferation of human androgen-independent prostate cancer cell line PC3 in vitro and in vivo by a cell cycle regulation pathway.

  13. Experimental Evidence of Persistent Androgen-Receptor-Dependency in Castration-Resistant Prostate Cancer

    OpenAIRE

    Osamu Ogawa; Tomomi Kamba; Takahiro Inoue; Takashi Kobayashi

    2013-01-01

    In the majority of castration-resistant prostate cancer (CRPC), prostate-specific antigen (PSA), product of a gene that is almost exclusively regulated by the androgen receptor (AR), still acts as a serum marker reflecting disease burden, indicating that AR signaling is activated even under castrate level of serum androgen. Accumulated evidence shows that transcriptional ability of AR is activated both in ligand-dependent and -independent manners in CRPC cells. Some androgen-independent subli...

  14. Influence of obesity and androgen deficiency on prostatic blood circulation

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2012-01-01

    Full Text Available In Study at 120 Diabetes Mellitus II type men the high frequency Obesity (71,7% and Androgen Deficiency (52,8—64,5% of the patients depending on a degree of the indemnification and them pathogenic authentic communications were shown. The blood level of total testosterone was represented by the critical factor of Prostatic arterial Blood Circulation. Obesity and Androgen Deficiency are seem as independent risk factors to development of ischemic prostatopathy, such as Prostatic blood circulation Disorders can develop earlier than other variants of the diabetic microangiophaty.

  15. From AR to c-Met: Androgen deprivation leads to a signaling pathway switch in prostate cancer cells

    OpenAIRE

    Liu, Tiancheng; Mendes, Desiree E.; Berkman, Clifford E.

    2013-01-01

    Elucidating the role of androgen deprivation in the transition from androgen-dependence to independence may enable the development of more specific therapeutic strategies against prostate cancer. Our previous in vitro model was employed to further assess the effects of continuous androgen-deprivation on prostate cancer cells (LNCaP) with respect to both androgen receptor (AR) and c-Met expression. The results indicated that long-term androgen deprivation resulted in a signaling pathway switch...

  16. Androgen-independent effects of Serenoa repens extract (Prostasan®) on prostatic epithelial cell proliferation and inflammation

    DEFF Research Database (Denmark)

    Iglesias-Gato, Diego; Carsten, Tober; Vesterlund, Mattias;

    2012-01-01

    Extracts from Serenoa repens are widely used for the treatment of benign prostatic hyperplasia (BPH) and traditionally for prostatitis. In the present study we evaluated the biological effects of Serenoa repens extract (Prostasan®) on prostate cells beyond its known antiandrogenic actions. Prosta...

  17. Androgen receptor: structure, role in prostate cancer and drug discovery

    OpenAIRE

    Tan, MH Eileen; Li, Jun; Xu, H. Eric; Melcher, Karsten; Yong, Eu-Leong

    2014-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer ...

  18. MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A

    OpenAIRE

    Sun, T; Wang, X; He, HH; Sweeney, CJ; Liu, SX; Brown, M.; Balk, S.; Lee, G-SM; Kantoff, PW

    2013-01-01

    Hormone-sensitive prostate cancer typically progresses to castration resistant prostate cancer (CRPC) after the androgen deprivation therapy. We investigated the impact of microRNAs (miRs) in the transition of prostate cancer to CRPC. MiR-221/-222 was highly expressed in bone metastatic CRPC tumor specimens. We previously demonstrated that transient overexpression of miR-221/-222 in LNCaP promoted the development of the CRPC phenotype. In current study, we show that stably overexpressing miR-...

  19. A promoting role of androgen receptor in androgen-sensitive and -insensitive prostate cancer cells

    OpenAIRE

    Li, Tzu-Huey; Zhao, Hongjuan; Peng, Yue; Beliakoff, Jason; James D Brooks; Sun, Zijie

    2007-01-01

    Although the vital role of the androgen receptor (AR) has been well demonstrated in primary prostate cancers, its role in the androgen-insensitive prostate cancers still remains unclear. Here, we used a small hairpin RNA approach to directly assess AR activity in prostate cancer cells. Reduction of AR expression in the two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC4, significantly decreased AR-mediated transcription and cell growth. Intriguingly, in two androgen-insensitive...

  20. Androgens and androgen receptors in prostatic cancer

    NARCIS (Netherlands)

    O.G.J.M. van Aubel (Olav)

    1989-01-01

    textabstractOur understanding of the testicular control of growth and functioning of the accessory sex glands began with an observation in the 18th century of John Hunter (1), who discovered in animals the endocrine dependency of the prostate. He demonstrated that castration in experimental animals

  1. Pomegranate Juice Metabolites, Ellagic Acid and Urolithin A, Synergistically Inhibit Androgen-Independent Prostate Cancer Cell Growth via Distinct Effects on Cell Cycle Control and Apoptosis

    Directory of Open Access Journals (Sweden)

    Roberto Vicinanza

    2013-01-01

    Full Text Available Ellagitannins (ETs from pomegranate juice (PJ are bioactive polyphenols with chemopreventive potential against prostate cancer (PCa. ETs are not absorbed intact but are partially hydrolyzed in the gut to ellagic acid (EA. Colonic microflora can convert EA to urolithin A (UA, and EA and UA enter the circulation after PJ consumption. Here, we studied the effects of EA and UA on cell proliferation, cell cycle, and apoptosis in DU-145 and PC-3 androgen-independent PCa cells and whether combinations of EA and UA affected cell proliferation. EA demonstrated greater dose-dependent antiproliferative effects in both cell lines compared to UA. EA induced cell cycle arrest in S phase associated with decreased cyclin B1 and cyclin D1 levels. UA induced a G2/M arrest and increased cyclin B1 and cdc2 phosphorylation at tyrosine-15, suggesting inactivation of the cyclin B1/cdc2 kinase complex. EA induced apoptosis in both cell lines, while UA had a less pronounced proapoptotic effect only in DU-145. Cotreatment with low concentrations of EA and UA dramatically decreased cell proliferation, exhibiting synergism in PC-3 cells evaluated by isobolographic analysis and combination index. These data provide information on pomegranate metabolites for the prevention of PCa recurrence, supporting the role of gut flora-derived metabolites for cancer prevention.

  2. Prostate specific antigen gene expression in androgen insensitive prostate carcinoma subculture cell line.

    Science.gov (United States)

    Tsui, Ke-Hung; Feng, Tsui-Hsia; Chung, Li-Chuan; Chao, Chun-Hsiang; Chang, Phei-Lang; Juang, Horng-Heng

    2008-01-01

    A novel prostate cancer cell line (PC-J) was isolated from an androgen independent non-prostate specific antigen (non-PSA) producing carcinoma cell line. The homologous correlation between PC-J and PC-3 was determined by short tandem repeat analysis. The PSA promoter activity was detected by transient expression assay in the PC-J and LNCaP cells but not in androgen insensitive PC-3 cells. When the PC-J cells were cotransfected with androgen receptor, androgen receptor coactivators and PSA reporter vector cells, the reporter assays indicated that nuclear receptor coactivator 4 (NCOA4) but not androgen receptor activator 24 (ARA24) increased the sensitivity and maximum stimulation of dihydrotestosterone (DHT)-inducing PSA promoter activity. The RT-PCR assays revealed that the expression of several tumor markers, including interleukin-6, prostate stem cell antigen (PSCA), prostate epithelium-specific Ets transcription factor (PDEF) and matriptase, was lower in the PC-J cells than in the PC-3 cells. This cell model elucidated the regulation of PSA expression and enabled comparison of the gene profile at different stages of metastasis in prostatic carcinoma.

  3. Transcriptional network of androgen receptor in prostate cancer progression.

    Science.gov (United States)

    Takayama, Ken-ichi; Inoue, Satoshi

    2013-08-01

    The androgen receptor belongs to the nuclear receptor superfamily and functions as a ligand-dependent transcription factor. It binds to the androgen responsive element and recruits coregulatory factors to modulate gene transcription. In addition, the androgen receptor interacts with other transcription factors, such as forkhead box A1, and other oncogenic signaling pathway molecules that bind deoxyribonucleic acid and regulate transcription. Androgen receptor signaling plays an important role in the development of prostate cancer. Prostate cancer cells proliferate in an androgen-dependent manner, and androgen receptor blockade is effective in prostate cancer therapy. However, patients often progress to castration-resistant prostate cancer with elevated androgen receptor expression and hypersensitivity to androgen. Recently, comprehensive analysis tools, such as complementary DNA microarray, chromatin immunoprecipitation-on-chip and chromatin immunoprecipitation-sequence, have described the androgen-mediated diverse transcriptional program and gene networks in prostate cancer. Furthermore, functional and clinical studies have shown that some of the androgen receptor-regulated genes could be prognostic markers and potential therapeutic targets for the treatment of prostate cancer, particularly castration-resistant prostate cancer. Thus, identifying androgen receptor downstream signaling events and investigating the regulation of androgen receptor activity is critical for understanding the mechanism of carcinogenesis and progression to castration-resistant prostate cancer.

  4. Overexpression of lysine-specific demethylase 1 promotes androgen-independent transition of human prostate cancer LNCaP cells through activation of the AR signaling pathway and suppression of the p53 signaling pathway.

    Science.gov (United States)

    Li, Xuechao; Li, Tao; Chen, Dehong; Zhang, Peng; Song, Yarong; Zhu, Hongxue; Xiao, Yajun; Xing, Yifei

    2016-01-01

    Lysine-specific demethylase 1 (LSD1) is the first defined histone demethylase, and was found to be closely correlated with the development and progression of various types of cancers, including prostate cancer (PCa). Previous research suggests that LSD1 is closely related with cell proliferation, angiogenesis, migration and invasion in PCa. However, it remains to be elucidated whether LSD1 is correlated with androgen-independent (AI) transition of PCa under androgen-ablated conditions. The present study aimed to investigate the correlation of LSD1 expression with AI transition of human androgen-dependent PCa LNCaP cells. Our data showed that LSD1 was overexpressed in human PCa specimens and in AI PCa LNCaP-AI cells, which were established through a three-month continuous culture of LNCaP cells in androgen-deprived medium. Under androgen-deprived conditions, LNCaP-AI cells grew perfectly with less apoptosis and G0/G1 cell cycle arrest. Overexpression of LSD1 protected the LNCaP cells from androgen deprivation-induced apoptosis and G0/G1 arrest, while knockdown of LSD1 drove LNCaP-AI cells into a higher rate of apoptosis and G0/G1 arrest. Furthermore, LSD1 was found to regulate the androgen receptor (AR) and p53 signaling pathways via demethylation, subsequently influencing apoptosis and cell cycle progression. These findings revealed that overexpression of LSD1 promoted AI transition of PCa LNCaP cells under androgen-ablated conditions via activation of the AR signaling pathway and suppression of the p53 signaling pathway. PMID:26534764

  5. Cardiac glycosides induce resistance to tubulin-dependent anticancer drugs in androgen-independent human prostate cancer.

    Science.gov (United States)

    Huang, Dong-Ming; Guh, Jih-Hwa; Huang, Yao-Ting; Chueh, Shih-Chieh; Wang, Hui-Po; Teng, Che-Ming

    2002-01-01

    Due to high prevalence and mortality and the lack of effective therapies, prostate cancer is one of the most crucial health problems in men. Drug resistance aggravates the situation, not only in human prostate cancer but also in other cancers. In this study, we report for the first time that cardiac glycosides (e.g. ouabain and digitoxin) induced resistance of human prostate cancer cells (PC-3) in vitro to tubulin-binding anticancer drugs, such as paclitaxel, colchicine, vincristine and vinblastine. Cardiac glycosides exhibited amazing ability to reverse the G2/M arrest of the cell cycle and cell apoptosis induced by tubulin-binding agents. However, neither ionomycin (a Ca(2+) ionophore) nor veratridine (a Na(+) ionophore) mimicked the preventive action of cardiac glycosides, indicating that elevation of the intracellular Ca(2+) concentration and Na(+) accumulation were not involved in the cardiac glycoside action. Furthermore, cardiac glycosides showed little influence on the effects induced by actinomycin D, anisomycin and doxorubicin, suggesting selectivity for microtubule-targeted anticancer drugs. Using in situ immunofluorescent detection of mitotic spindles, our data showed that cardiac glycosides diminished paclitaxel-induced accumulation of microtubule spindles; however, in a non-cell assay system, cardiac glycosides had little influence on colchicine- and paclitaxel-induced microtubule dynamics. Using an isotope-labeled assay method, we found that ouabain modestly but significantly inhibited the transport of [(14)C]paclitaxel from the cytosol into the nucleus. It is suggested that cardiac glycosides inhibit the G2/M arrest induced by tubulin-binding anticancer drugs via an indirect blockade on microtubule function. The decline in transport of these drugs into the nucleus may partly explain the action of cardiac glycosides. PMID:12218360

  6. Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells.

    Science.gov (United States)

    McNaughton, Melissa; Pitman, Melissa; Pitson, Stuart M; Pyne, Nigel J; Pyne, Susan

    2016-03-29

    Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest.

  7. Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells

    Science.gov (United States)

    McNaughton, Melissa; Pitman, Melissa; Pitson, Stuart M.; Pyne, Nigel J.; Pyne, Susan

    2016-01-01

    Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest. PMID:26934645

  8. A clinical data validated mathematical model of prostate cancer growth under intermittent androgen suppression therapy

    Science.gov (United States)

    Portz, Travis; Kuang, Yang; Nagy, John D.

    2012-03-01

    Prostate cancer is commonly treated by a form of hormone therapy called androgen suppression. This form of treatment, while successful at reducing the cancer cell population, adversely affects quality of life and typically leads to a recurrence of the cancer in an androgen-independent form. Intermittent androgen suppression aims to alleviate some of these adverse affects by cycling the patient on and off treatment. Clinical studies have suggested that intermittent therapy is capable of maintaining androgen dependence over multiple treatment cycles while increasing quality of life during off-treatment periods. This paper presents a mathematical model of prostate cancer to study the dynamics of androgen suppression therapy and the production of prostate-specific antigen (PSA), a clinical marker for prostate cancer. Preliminary models were based on the assumption of an androgen-independent (AI) cell population with constant net growth rate. These models gave poor accuracy when fitting clinical data during simulation. The final model presented hypothesizes an AI population with increased sensitivity to low levels of androgen. It also hypothesizes that PSA production is heavily dependent on androgen. The high level of accuracy in fitting clinical data with this model appears to confirm these hypotheses, which are also consistent with biological evidence.

  9. Androgen receptor signaling and mutations in prostate cancer

    OpenAIRE

    Koochekpour, Shahriar

    2010-01-01

    Normal and neoplastic growth of the prostate gland are dependent on androgen receptor (AR) expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-indep...

  10. Activation of two mutant androgen receptors from human prostatic carcinoma by adrenal androgens and metabolic derivatives of testosterone.

    Science.gov (United States)

    Culig, Z; Stober, J; Gast, A; Peterziel, H; Hobisch, A; Radmayr, C; Hittmair, A; Bartsch, G; Cato, A C; Klocker, H

    1996-01-01

    The androgen receptor (AR) plays a central regulatory role in prostatic carcinoma and is a target of androgen ablation therapy. Recent detection of mutant receptors in tumor specimens suggest a contribution of AR alterations to progression towards androgen independence. In a specimen derived from metastatic prostate cancer we have reported a point mutation in the AR gene that leads to a single amino acid exchange in the ligand binding domain of the receptor. Another amino acid exchange resulting from a point mutation was also identified 15 amino acids away from our mutation. This mutation was detected in the AR gene isolated from an organ-confined prostatic tumor. Here we report the functional characterization of the two mutant receptors in the presence of adrenal androgens and testosterone metabolites. These studies were performed by cotransfecting androgen-responsive reporter genes and either the wild-type or mutant AR expression vectors into receptor negative DU-145 and CV-1 cells. The indicator genes used consisted of the promoter of the androgen-inducible prostate-specific antigen gene or the C' Delta9 enhancer fragment from the promoter of the mouse sex-limited protein driving the expression of the bacterial chloramphenicol acetyl transferase gene. Cotransfection-transactivation assays revealed that the adrenal androgen androstenedione and two products of testosterone metabolism, androsterone and androstandiol, induced reporter gene activity more efficiently in the presence of the mutant receptors than in the presence of the wild-type receptor. No difference between wild-type and mutant receptors was observed in the presence of the metabolite androstandione. The interaction of receptor-hormone complexes with target DNA was studied in vitro by electrophoretic mobility shift assays (EMSA). Dihydrotestosterone and the synthetic androgen mibolerone induced a faster migrating complex with all receptors, whereas the androgen metabolite androstandione induced this

  11. Androgen Deprivation-Induced Senescence Promotes Outgrowth of Androgen-Refractory Prostate Cancer Cells

    OpenAIRE

    Burton, Dominick G. A.; Giribaldi, Maria G.; Anisleidys Munoz; Katherine Halvorsen; Asmita Patel; Merce Jorda; Carlos Perez-Stable; Priyamvada Rai

    2013-01-01

    Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refra...

  12. The liver X receptor agonist T0901317 acts as androgen receptor antagonist in human prostate cancer cells

    International Nuclear Information System (INIS)

    T0901317 is a potent non-steroidal synthetic liver X receptor (LXR) agonist. T0901317 blocked androgenic stimulation of the proliferation of androgen-dependent LNCaP 104-S cells and androgenic suppression of the proliferation of androgen-independent LNCaP 104-R2 cells, inhibited the transcriptional activation of an androgen-dependent reporter gene by androgen, and suppressed gene and protein expression of prostate specific antigen (PSA), a target gene of androgen receptor (AR) without affecting gene and protein expression of AR. T0901317 also inhibited binding of a radiolabeled androgen to AR, but inhibition was much weaker compared to the effect of the antiandrogens, bicalutamide and hydroxyflutamide. The LXR agonist T0901317, therefore, acts as an antiandrogen in human prostate cancer cells

  13. Genes regulated by androgen in the rat ventral prostate

    OpenAIRE

    Wang, Zhou; Tufts, Rachel; Haleem, Riffat; Cai, Xiaoyan

    1997-01-01

    Genes that are regulated by androgen in the prostate were studied in the rat. Four of the less than 10 genes that are down-regulated by androgen in the ventral prostate of a 7-day castrated rat were identified; their mRNAs decayed with identical kinetics. Twenty-five of the estimated 56 genes that are up-regulated by androgen in the castrated prostate have been isolated. The up-regulated genes fall into two kinetic types. Early genes are significantly up-regulated by 6.5 hr whereas the delaye...

  14. Sphingosine kinase-1 is central to androgen-regulated prostate cancer growth and survival.

    Directory of Open Access Journals (Sweden)

    Audrey Dayon

    Full Text Available BACKGROUND: Sphingosine kinase-1 (SphK1 is an oncogenic lipid kinase notably involved in response to anticancer therapies in prostate cancer. Androgens regulate prostate cancer cell proliferation, and androgen deprivation therapy is the standard of care in the management of patients with advanced disease. Here, we explored the role of SphK1 in the regulation of androgen-dependent prostate cancer cell growth and survival. METHODOLOGY/PRINCIPAL FINDINGS: Short-term androgen removal induced a rapid and transient SphK1 inhibition associated with a reduced cell growth in vitro and in vivo, an event that was not observed in the hormono-insensitive PC-3 cells. Supporting the critical role of SphK1 inhibition in the rapid effect of androgen depletion, its overexpression could impair the cell growth decrease. Similarly, the addition of dihydrotestosterone (DHT to androgen-deprived LNCaP cells re-established cell proliferation, through an androgen receptor/PI3K/Akt dependent stimulation of SphK1, and inhibition of SphK1 could markedly impede the effects of DHT. Conversely, long-term removal of androgen support in LNCaP and C4-2B cells resulted in a progressive increase in SphK1 expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE-like cell phenotype. Importantly, inhibition of the PI3K/Akt pathway--by negatively impacting SphK1 activity--could prevent NE differentiation in both cell models, an event that could be mimicked by SphK1 inhibitors. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SphK1 activity. CONCLUSIONS/SIGNIFICANCE: We report the first evidence that androgen deprivation induces a differential effect on SphK1 activity in hormone-sensitive prostate cancer cell models. These results also suggest that SphK1 activation upon chronic androgen deprivation may serve as a

  15. GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor

    International Nuclear Information System (INIS)

    Research highlights: → GLI1, which play a central role in sonic hedgehog signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor-mediated transactivation. → GLI1 directly interacts with AR. → SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from an androgen-dependent to an androgen-independent state. -- Abstract: Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from an androgen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling.

  16. GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Guangchun; Goto, Yutaka; Sakamoto, Ryuichi; Tanaka, Kimitaka; Matsubara, Eri [Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582 (Japan); Nakamura, Masafumi [Department of Cancer Therapy and Research, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582 (Japan); Zheng, Hong [School of Pharmacy, Second Military Medical University, Shanghai 200433 (China); Lu, Jian [Department of Pathophysiology, Second Military Medical University, Shanghai 200433 (China); Takayanagi, Ryoichi [Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582 (Japan); Nomura, Masatoshi, E-mail: nomura@med.kyushu-u.ac.jp [Department of Medicine and Bioregulatory Science, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582 (Japan)

    2011-01-21

    Research highlights: {yields} GLI1, which play a central role in sonic hedgehog signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor-mediated transactivation. {yields} GLI1 directly interacts with AR. {yields} SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from an androgen-dependent to an androgen-independent state. -- Abstract: Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from an androgen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling.

  17. Sulforaphane increases the efficacy of anti-androgens by rapidly decreasing androgen receptor levels in prostate cancer cells.

    Science.gov (United States)

    Khurana, Namrata; Talwar, Sudha; Chandra, Partha K; Sharma, Pankaj; Abdel-Mageed, Asim B; Mondal, Debasis; Sikka, Suresh C

    2016-10-01

    Prostate cancer (PCa) cells utilize androgen for their growth. Hence, androgen deprivation therapy (ADT) using anti-androgens, e.g. bicalutamide (BIC) and enzalutamide (ENZ), is a mainstay of treatment. However, the outgrowth of castration resistant PCa (CRPC) cells remains a significant problem. These CRPC cells express androgen receptor (AR) and utilize the intratumoral androgen towards their continued growth and invasion. Sulforaphane (SFN), a naturally occurring isothiocyanate found in cruciferous vegetables, can decrease AR protein levels. In the present study, we tested the combined efficacy of anti-androgens and SFN in suppressing PCa cell growth, motility and clonogenic ability. Both androgen-dependent (LNCaP) and androgen-independent (C4-2B) cells were used to monitor the effects of BIC and ENZ, alone and in combination with SFN. Co-exposure to SFN significantly (pcell migration. In addition, long-term exposures (14 days) to much lower concentrations of these agents, SFN (0.2 µM), BIC (1 µM) and/or ENZ (0.4 µM) significantly (pcells. PMID:27499349

  18. The relationship between cb1-b gene and androgen independent prostate cancer during the immunotherapy%Cb1-b基因与免疫治疗激素非依赖性前列腺癌

    Institute of Scientific and Technical Information of China (English)

    李学峰; 史振铎

    2010-01-01

    前列腺肿瘤主要的治疗手段包括手术、放化疗、内分泌治疗等.大多数晚期前列腺癌往往转变为激素非依赖性,对于激素非依赖性前列腺癌(Androgen Independent Prostate Cancer,AIPC)目前缺乏有效的治疗手段.研究发现Cb1-b(Casitas B cell lymphoma-b)基因在调节抗肿瘤免疫方面发挥着重要作用.通过沉默T细胞Cb1-b基因的表达从而增强机体的抗肿瘤免疫有望在AIPC治疗上实现重大突破.

  19. Androgen deprivation promotes intratumoral synthesis of dihydrotestosterone from androgen metabolites in prostate cancer

    OpenAIRE

    Fumio Ishizaki; Tsutomu Nishiyama; Takashi Kawasaki; Yoshimichi Miyashiro; Noboru Hara; Itsuhiro Takizawa; Makoto Naito; Kota Takahashi

    2013-01-01

    Intratumoral synthesis of dihydrotestosterone (DHT) from precursors cannot completely explain the castration resistance of prostate cancer. We showed that DHT was intratumorally synthesized from the inactive androgen metabolites 5α-androstane-3α/β,17β-diol (3α/β-diol) in prostate cancer cells via different pathways in a concentration-dependent manner. Additionally, long-term culture in androgen-deprived media increased transcriptomic expression of 17β-hydroxysteroid dehydrogenase type 6 (HSD1...

  20. Androgen receptor: structure, role in prostate cancer and drug discovery.

    Science.gov (United States)

    Tan, M H Eileen; Li, Jun; Xu, H Eric; Melcher, Karsten; Yong, Eu-leong

    2015-01-01

    Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein. PMID:24909511

  1. Stilbenes inhibit androgen receptor expression in 22Rv1 castrate-resistant prostate cancer cells

    Science.gov (United States)

    Androgen receptor (AR) signaling plays an important role in the development and progression of prostate cancer (PCa). Importantly, AR continues to be expressed in advanced stages of castrate-resistant PCa (CRPC), where it can have ligand- independent activity. Identification of naturally occurring s...

  2. Androgen regulated genes in human prostate xenografts in mice: relation to BPH and prostate cancer.

    Directory of Open Access Journals (Sweden)

    Harold D Love

    Full Text Available Benign prostatic hyperplasia (BPH and prostate carcinoma (CaP are linked to aging and the presence of androgens, suggesting that androgen regulated genes play a major role in these common diseases. Androgen regulation of prostate growth and development depends on the presence of intact epithelial-stromal interactions. Further, the prostatic stroma is implicated in BPH. This suggests that epithelial cell lines are inadequate to identify androgen regulated genes that could contribute to BPH and CaP and which could serve as potential clinical biomarkers. In this study, we used a human prostate xenograft model to define a profile of genes regulated in vivo by androgens, with an emphasis on identifying candidate biomarkers. Benign transition zone (TZ human prostate tissue from radical prostatectomies was grafted to the sub-renal capsule site of intact or castrated male immunodeficient mice, followed by the removal or addition of androgens, respectively. Microarray analysis of RNA from these tissues was used to identify genes that were; 1 highly expressed in prostate, 2 had significant expression changes in response to androgens, and, 3 encode extracellular proteins. A total of 95 genes meeting these criteria were selected for analysis and validation of expression in patient prostate tissues using quantitative real-time PCR. Expression levels of these genes were measured in pooled RNAs from human prostate tissues with varying severity of BPH pathologic changes and CaP of varying Gleason score. A number of androgen regulated genes were identified. Additionally, a subset of these genes were over-expressed in RNA from clinical BPH tissues, and the levels of many were found to correlate with disease status. Our results demonstrate the feasibility, and some of the problems, of using a mouse xenograft model to characterize the androgen regulated expression profiles of intact human prostate tissues.

  3. Unraveling the Complexities of Androgen Receptor Signaling in Prostate Cancer Cells

    OpenAIRE

    Heemers, Hannelore V.; Tindall, Donald J.

    2009-01-01

    Androgen signaling is critical for proliferation of prostate cancer cells but cannot be fully inhibited by current androgen deprivation therapies. A study by Xu et al. in this issue of Cancer Cell provides insights into the complexities of androgen signaling in prostate cancer and suggests avenues to target a subset of androgen-sensitive genes.

  4. Outcome analysis of 300 prostate cancer patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy

    International Nuclear Information System (INIS)

    Purpose: Neoadjuvant androgen deprivation and radical radiotherapy is an established treatment for localized prostate carcinoma. This study sought to analyze the outcomes of patients treated with relatively low-dose hypofractionated radiotherapy. Methods and Materials: Three hundred patients with T1-T3 prostate cancer were treated between 1996 and 2001. Patients were prescribed 3 months of neoadjuvant androgen deprivation before receiving 5250 cGy in 20 fractions. Patients' case notes and the oncology database were used to retrospectively assess outcomes. Median follow-up was 58 months. Results: Patients presented with prostate cancer with poorer prognostic indicators than that reported in other series. At 5 years, the actuarial cause-specific survival rate was 83.2% and the prostate-specific antigen (PSA) relapse rate was 57.3%. Metastatic disease had developed in 23.4% of patients. PSA relapse continued to occur 5 years from treatment in all prognostic groups. Independent prognostic factors for relapse included treatment near the start of the study period, neoadjuvant oral anti-androgen monotherapy rather than neoadjuvant luteinizing hormone releasing hormone therapy, and diagnosis through transurethral resection of the prostate rather than transrectal ultrasound. Conclusion: This is the largest reported series of patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy in the United Kingdom. Neoadjuvant hormonal therapy did not appear to adequately compensate for the relatively low effective radiation dose used

  5. 3,3'-Diindolylmethane (DIM) and its ring-substituted halogenated analogs (ring-DIMs) induce differential mechanisms of survival and death in androgen-dependent and -independent prostate cancer cells.

    Science.gov (United States)

    Goldberg, Alexander A; Draz, Hossam; Montes-Grajales, Diana; Olivero-Verbél, Jesus; Safe, Stephen H; Sanderson, J Thomas

    2015-05-01

    We recently reported that novel ring-substituted analogs of 3,3'-diindolylmethane (ring-DIMs) induce apoptosis and necrosis in androgen-dependent and -independent prostate cancer cells. In this paper, we have focused on the mechanism(s) associated with ring-DIM-mediated cell death, and on identifying the specific intracellular target(s) of these compounds. The 4,4'- and 7,7'-dichloroDIMs and 4,4'- and 7,7'-dibromoDIMs induced the death of LNCaP, C42B and DU145 prostate cancer cells, but not that of immortalized normal human prostate epithelial (RWPE-1) cells. Ring-DIMs caused the early loss of mitochondrial membrane potential (MMP) and decreased mitochondrial ATP generation in prostate cancer cells. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore, inhibited ring-DIM-mediated cell death, and salubrinal, an inhibitor of ER stress, inhibited cell death mediated only by 4,4'-dihaloDIMs. We found that although salubrinal did not inhibit the onset of ER stress, it prevented 4,4'-dibromoDIM mediated loss of MMP. Salubrinal potentiated cell death in response to 7,7'-dihaloDIMs and DIM, and this effect concurred with increased loss of MMP. Using in silico 3-D docking affinity analysis, we identified Ca2+/calmodulin-dependent kinase II (CaMKII) as a potential direct target for the most toxic ring-DIM, 4,4'-dibromoDIM. An inhibitor of CaMKII, KN93, but not its inactive analog KN92, abrogated cell death mediated by 4,4'-dibromoDIM. The ring-DIMs induced ER stress and autophagy, but these processes were not necessary for ring-DIM-mediated cell death. Inhibition of autophagy with bafilomycin A1, 3-methyladenine or by LC3B gene silencing sensitized LNCaP and C42B, but not ATG5-deficient DU145 cells to ring-DIM- and DIM-mediated cell death. We propose that autophagy induced by the ring-DIMs and DIM has a cytoprotective function in prostate cancer cells. PMID:26124925

  6. 3,3′-Diindolylmethane (DIM) and its ring-substituted halogenated analogs (ring-DIMs) induce differential mechanisms of survival and death in androgen-dependent and –independent prostate cancer cells

    Science.gov (United States)

    Montes-Grajales, Diana; Olivero-Verbél, Jesus; Safe, Stephen H.; Sanderson, J. Thomas

    2015-01-01

    We recently reported that novel ring-substituted analogs of 3,3′-diindolylmethane (ring-DIMs) induce apoptosis and necrosis in androgen-dependent and –independent prostate cancer cells. In this paper, we have focused on the mechanism(s) associated with ring-DIM-mediated cell death, and on identifying the specific intracellular target(s) of these compounds. The 4,4′- and 7,7′-dichloroDIMs and 4,4′- and 7,7′-dibromoDIMs induced the death of LNCaP, C42B and DU145 prostate cancer cells, but not that of immortalized normal human prostate epithelial (RWPE-1) cells. Ring-DIMs caused the early loss of mitochondrial membrane potential (MMP) and decreased mitochondrial ATP generation in prostate cancer cells. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore, inhibited ring-DIM-mediated cell death, and salubrinal, an inhibitor of ER stress, inhibited cell death mediated only by 4,4′-dihaloDIMs. We found that although salubrinal did not inhibit the onset of ER stress, it prevented 4,4′-dibromoDIM mediated loss of MMP. Salubrinal potentiated cell death in response to 7,7′-dihaloDIMs and DIM, and this effect concurred with increased loss of MMP. Using in silico 3-D docking affinity analysis, we identified Ca2+/calmodulin-dependent kinase II (CaMKII) as a potential direct target for the most toxic ring-DIM, 4,4′-dibromoDIM. An inhibitor of CaMKII, KN93, but not its inactive analog KN92, abrogated cell death mediated by 4,4′-dibromoDIM. The ring-DIMs induced ER stress and autophagy, but these processes were not necessary for ring-DIM-mediated cell death. Inhibition of autophagy with bafilomycin A1, 3-methyladenine or by LC3B gene silencing sensitized LNCaP and C42B, but not ATG5-deficient DU145 cells to ring-DIM- and DIM-mediated cell death. We propose that autophagy induced by the ring-DIMs and DIM has a cytoprotective function in prostate cancer cells. PMID:26124925

  7. Looking beyond Androgen Receptor Signaling in the Treatment of Advanced Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Benjamin Sunkel

    2014-01-01

    Full Text Available This review will provide a description of recent efforts in our laboratory contributing to a general goal of identifying critical determinants of prostate cancer growth in both androgen-dependent and -independent contexts. Important outcomes to date have indicated that the sustained activation of AR transcriptional activity in castration-resistant prostate cancer (CRPC cells results in a gene expression profile separate from the androgen-responsive profile of androgen-dependent prostate cancer (ADPC cells. Contributing to this reprogramming is enhanced FoxA1 recruitment of AR to G2/M phase target gene loci and the enhanced chromatin looping of CRPC-specific gene regulatory elements facilitated by PI3K/Akt-phosphorylated MED1. We have also observed a role for FoxA1 beyond AR signaling in driving G1/S phase cell cycle progression that relies on interactions with novel collaborators MYBL2 and CREB1. Finally, we describe an in-depth mechanism of GATA2-mediated androgen-responsive gene expression in both ADPC and CRPC cells. Altogether these efforts provide evidence to support the development of novel prostate cancer therapeutics that address downstream targets of AR activity as well as AR-independent drivers of disease-relevant transcription programs.

  8. Identification of novel androgen receptor target genes in prostate cancer

    Directory of Open Access Journals (Sweden)

    Gerald William L

    2007-06-01

    Full Text Available Abstract Background The androgen receptor (AR plays critical roles in both androgen-dependent and castrate-resistant prostate cancer (PCa. However, little is known about AR target genes that mediate the receptor's roles in disease progression. Results Using Chromatin Immunoprecipitation (ChIP Display, we discovered 19 novel loci occupied by the AR in castrate resistant C4-2B PCa cells. Only four of the 19 AR-occupied regions were within 10-kb 5'-flanking regulatory sequences. Three were located up to 4-kb 3' of the nearest gene, eight were intragenic and four were in gene deserts. Whereas the AR occupied the same loci in C4-2B (castrate resistant and LNCaP (androgen-dependent PCa cells, differences between the two cell lines were observed in the response of nearby genes to androgens. Among the genes strongly stimulated by DHT in C4-2B cells – D-dopachrome tautomerase (DDT, Protein kinase C delta (PRKCD, Glutathione S- transferase theta 2 (GSTT2, Transient receptor potential cation channel subfamily V member 3 (TRPV3, and Pyrroline-5-carboxylate reductase 1 (PYCR1 – most were less strongly or hardly stimulated in LNCaP cells. Another AR target gene, ornithine aminotransferase (OAT, was AR-stimulated in a ligand-independent manner, since it was repressed by AR siRNA knockdown, but not stimulated by DHT. We also present evidence for in vivo AR-mediated regulation of several genes identified by ChIP Display. For example, PRKCD and PYCR1, which may contribute to PCa cell growth and survival, are expressed in PCa biopsies from primary tumors before and after ablation and in metastatic lesions in a manner consistent with AR-mediated stimulation. Conclusion AR genomic occupancy is similar between LNCaP and C4-2B cells and is not biased towards 5' gene flanking sequences. The AR transcriptionally regulates less than half the genes nearby AR-occupied regions, usually but not always, in a ligand-dependent manner. Most are stimulated and a few are

  9. Neural protein gamma-synuclein interacting with androgen receptor promotes human prostate cancer progression

    International Nuclear Information System (INIS)

    Gamma-synuclein (SNCG) has previously been demonstrated to be significantly correlated with metastatic malignancies; however, in-depth investigation of SNCG in prostate cancer is still lacking. In the present study, we evaluated the role of SNCG in prostate cancer progression and explored the underlying mechanisms. First, alteration of SNCG expression in LNCaP cell line to test the ability of SNCG on cellular properties in vitro and vivo whenever exposing with androgen or not. Subsequently, the Dual-luciferase reporter assays were performed to evaluate whether the role of SNCG in LNCaP is through AR signaling. Last, the association between SNCG and prostate cancer progression was assessed immunohistochemically using a series of human prostate tissues. Silencing SNCG by siRNA in LNCaP cells contributes to the inhibition of cellular proliferation, the induction of cell-cycle arrest at the G1 phase, the suppression of cellular migration and invasion in vitro, as well as the decrease of tumor growth in vivo with the notable exception of castrated mice. Subsequently, mechanistic studies indicated that SNCG is a novel androgen receptor (AR) coactivator. It interacts with AR and promotes prostate cancer cellular growth and proliferation by activating AR transcription in an androgen-dependent manner. Finally, immunohistochemical analysis revealed that SNCG was almost undetectable in benign or androgen-independent tissues prostate lesions. The high expression of SNCG is correlated with peripheral and lymph node invasion. Our data suggest that SNCG may serve as a biomarker for predicting human prostate cancer progression and metastasis. It also may become as a novel target for biomedical therapy in advanced prostate cancer

  10. Clinical outcomes of anti-androgen withdrawal and subsequent alternative anti-androgen therapy for advanced prostate cancer following failure of initial maximum androgen blockade

    OpenAIRE

    MOMOZONO, HIROYUKI; Miyake, Hideaki; TEI, HIROMOTO; Harada, Ken-ichi; Fujisawa, Masato

    2016-01-01

    The present study aimed to investigate the significance of anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy in patients with advanced prostate cancer (PC) who relapsed after initial maximum androgen blockade (MAB). The present study evaluated the clinical outcomes of 272 consecutive advanced PC patients undergoing anti-androgen withdrawal and/or subsequent alternative anti-androgen therapy with flutamide following the failure of initial MAB using bicalutamide. With...

  11. The CXCL12/CXCR4 axis promotes ligand-independent activation of the androgen receptor.

    Science.gov (United States)

    Kasina, Sathish; Macoska, Jill A

    2012-04-01

    The molecular mechanisms responsible for the transition of some prostate cancers from androgen ligand-dependent to androgen ligand-independent are incompletely established. Molecules that are ligands for G protein coupled receptors (GPCRs) have been implicated in ligand-independent androgen receptor (AR) activation. The purpose of this study was to examine whether CXCL12, the ligand for the GPCR, CXCR4, might mediate prostate cancer cell proliferation through AR-dependent mechanisms involving functional transactivation of the AR in the absence of androgen. The results of these studies showed that activation of the CXCL12/CXCR4 axis promoted: The nuclear accumulation of both wild-type and mutant AR in several prostate epithelial cell lines; AR-dependent proliferative responses; nuclear accumulation of the AR co-regulator SRC-1 protein; SRC-1:AR protein:protein association; co-localization of AR and SRC-1 on the promoters of AR-regulated genes; AR- and SRC-1 dependent transcription of AR-regulated genes; AR-dependent secretion of the AR-regulated PSA protein; P13K-dependent phosphorylation of AR; MAPK-dependent phosphorylation of SRC-1, and both MAPK- and P13K-dependent secretion of the PSA protein, in the absence of androgen. Taken together, these studies identify CXCL12 as a novel, non-steroidal growth factor that promotes the growth of prostate epithelial cells through AR-dependent mechanisms in the absence of steroid hormones. These findings support the development of novel therapeutics targeting the CXCL12/CXCR4 axis as an ancillary to those targeting the androgen/AR axis to effectively treat castration resistant/recurrent prostate tumors.

  12. Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer.

    OpenAIRE

    Sehgal, I.; Powers, S.; B. Huntley; Powis, G; Pittelkow, M; Maihle, N J

    1994-01-01

    After therapeutic hormone deprivation, prostate cancer cells often develop androgen-insensitive growth through mechanisms thus far undefined. Neuropeptides have been previously implicated as growth factors in some prostate cancers. Here, we demonstrate that androgen-sensitive LNCaP human prostate cancer cells produce and secrete neurotensin following androgen withdrawal. We show that while LNCaP cells express the neurotensin receptor, only androgen-deprived cells exhibit a growth response to ...

  13. Hyperactive androgen receptor in prostate cancer, what does it mean for new therapy concepts?

    OpenAIRE

    Culig, Z.; Hobisch, A.; Hittmair, A; Radmayr, C.; Peterziel, H.; Bartsch, G; Cato, A. C. B.; Klocker, H

    1997-01-01

    Investigations on androgen signaling alterations in the late stages of prostate cancer revealed new molecular mechanisms that may be in part responsible for failure of endocrine therapy. Both primary and metastatic lesions from prostate cancer express androgen receptor protein. Amplification of androgen receptor gene occurs in a subset of prostate cancer patients. Several point mutations of androgen receptor gene have been described; they generate receptors whi...

  14. Andrographolide Targets Androgen Receptor Pathway in Castration-Resistant Prostate Cancer

    OpenAIRE

    Liu, Chengfei; Nadiminty, Nagalakshmi; Tummala, Ramakumar; Chun, Jae Yeon; Lou, Wei; Zhu, Yezi; Sun, Meng; Evans, Christopher P.; Zhou, Qinghua; Gao, Allen C.

    2011-01-01

    Androgen receptor (AR) signaling not only plays a pivotal role in the development of androgen-dependent prostate cancer but is also important in the growth and survival of castration-resistant prostate cancer (CRPC). The first line of treatment of androgen-dependent prostate cancer is the use of androgen deprivation therapy. However, most patients will eventually relapse due to development of CRPC. Thus, development of a strategy to target AR for treatment of CRPC is urgently needed. The auth...

  15. Detection of androgen receptor in human prostatic adenoma by autoradiography

    Energy Technology Data Exchange (ETDEWEB)

    Demura, Takayoshi; Sakashita, Shigeo; Takamura, Takao; Kuroda, Kazuhide (Asahikawa Medical Coll., Hokkaido (Japan))

    1982-09-01

    We developed a new amplified method to detect the localization of androgen receptors within the human prostatic tissue specimens. The tissue sections were treated with 50 ..mu..l of 100 nM tritiated dihydrotestosterone (/sup 3/H-DHT). The binding of /sup 3/H-DHT to receptors was demonstrated as silver grains on the stained tissue sections. The binding of /sup 3/H-DHT to the prostatic tissue was inhibited by additional non-radioactive DHT remarkably and by testosterone partially, but not affected by additional progesterone and 17..beta..-estradiol. No binding of /sup 3/H-DHT to the bladder tissue was found. These results showed that the binding of /sup 3/H-DHT to the prostatic tissue was a specific reaction of /sup 3/H-DHT and androgen receptor. Androgen receptors were seen in the nuclei and the cytoplasmas of glandular epithelial cells of prostate. However, stromal cells contained less abundant androgen receptors. The method reported here has several advantages in detecting the androgen receptor of the prostatic tissue in comparison with the radioreceptor assay and other histochemical methods. 1) The needle biopsied specimens are big enough to examine. 2) Morphological observations are also possible on the same specimen because the specimens are stained with hematoxylin simultaneously. Therefore, we can know the relative ratio of androgen receptor positive cells and negative cells. 3) Binding of /sup 3/H-DHT to the receptor with this method may be more specific than other histochemical methods, since binding of /sup 3/H-DHT to the receptor was inhibited by 200-fold excess of non-radioactive DHT. 4) Treatment of scintillator, fluorographic technique shortens the exposure periods. The exposure periods are approximately six to twelve times shorter than that of the conventional autoradiography.

  16. Antiandrogens and androgen depleting therapies in prostate cancer: novel agents for an established target

    OpenAIRE

    Chen, Yu; Clegg, Nicola J.; Scher, Howard I.

    2009-01-01

    Activation of the androgen receptor is critical for prostate cancer growth at all points in the illness. Currently therapies targeting the androgen receptor, including androgen depletion approaches and antiandrogens, do not completely inhibit androgen receptor activity. Prostate cancer cells develop resistance to castration by acquiring changes such as AR overexpression that result in reactivation of the receptor. Based on understanding of these resistance mechanisms and androgen synthesis pa...

  17. Androgen deprivation therapy for prostate cancer:not so simple

    Institute of Scientific and Technical Information of China (English)

    Nicholas N Tadros; Mark Garzotto

    2011-01-01

    @@ Prostate cancer(PC)is the second most diagnosed visceral malignancy in men worldwide, with over 900 000 new diagnoses each year.1 Approximately 50% of patients treated in industrialized nations will receive androgen deprivation therapy(ADT)at some point in their lifetimes.2

  18. Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor.

    Science.gov (United States)

    Zhang, Boyu; Kwon, Oh-Joon; Henry, Gervaise; Malewska, Alicia; Wei, Xing; Zhang, Li; Brinkley, William; Zhang, Yiqun; Castro, Patricia D; Titus, Mark; Chen, Rui; Sayeeduddin, Mohammad; Raj, Ganesh V; Mauck, Ryan; Roehrborn, Claus; Creighton, Chad J; Strand, Douglas W; Ittmann, Michael M; Xin, Li

    2016-09-15

    Prostate inflammation has been suggested as an etiology for benign prostatic hyperplasia (BPH). We show that decreased expression of the androgen receptor (AR) in luminal cells of human BPH specimens correlates with a higher degree of regional prostatic inflammation. However, the cause-and-effect relationship between the two events remains unclear. We investigated specifically whether attenuating AR activity in prostate luminal cells induces inflammation. Disrupting luminal cell AR signaling in mouse models promotes cytokine production cell-autonomously, impairs epithelial barrier function, and induces immune cell infiltration, which further augments local production of cytokines and chemokines including Il-1 and Ccl2. This inflammatory microenvironment promotes AR-independent prostatic epithelial proliferation, which can be abolished by ablating IL-1 signaling or depleting its major cellular source, the macrophages. This study demonstrates that disrupting luminal AR signaling promotes prostate inflammation, which may serve as a mechanism for resistance to androgen-targeted therapy for prostate-related diseases. PMID:27594448

  19. Wnt Inhibitory Factor 1 (Wif1) Is Regulated by Androgens and Enhances Androgen-Dependent Prostate Development

    OpenAIRE

    Keil, Kimberly P.; Mehta, Vatsal; Branam, Amanda M.; Abler, Lisa L.; Buresh-Stiemke, Rita A.; Joshi, Pinak S.; Schmitz, Christopher T.; Marker, Paul C.; Vezina, Chad M.

    2012-01-01

    Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-respons...

  20. Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions

    OpenAIRE

    Decker, Keith F.; Zheng, Dali; He, Yuhong; Bowman, Tamara; Edwards, John R.; Jia, Li

    2012-01-01

    The androgen receptor (AR) is a ligand-inducible transcription factor that mediates androgen action in target tissues. Upon ligand binding, the AR binds to thousands of genomic loci and activates a cell-type specific gene program. Prostate cancer growth and progression depend on androgen-induced AR signaling. Treatment of advanced prostate cancer through medical or surgical castration leads to initial response and durable remission, but resistance inevitably develops. In castration-resistant ...

  1. Effect of androgen withdrawal on activation of ERKs and expression of cell cycle regulation molecules in human prostate carcinoma cells

    Institute of Scientific and Technical Information of China (English)

    YE Ding-wei; LI Hui; TSENG Jane; CHAUVIN Priscilla; QIAN Song-xi; ZHENG Jia-fu; SUN Ying-hao; MA Yong-jiang

    2002-01-01

    Objective: To explore the possible mechanisms of growth regression of human androgen dependentprostate carcinoma cells caused by androgen withdrawal. Methods: After 24 h of treatment with 1×10-9mol/L dihydrotestosterone (DHT), the expression of phosphorylated ERK proteins and cell cycle regulationmolecules including CDK2, CDK4, CDK6 and P27kip1 in human androgen dependent prostate carcinoma cellline LNCaP was measured by Western blot analysis 0 h, 8 h and 24 h of after androgen withdrawal. Humanandrogen independent prostate carcinoma cell line PC-3 was also examined as control. Results: Down-regula-tion of phosphorylated ERK, CDK2, CDK4 and CDK6 and up-regulation of P27kip1 were found initially inLNCaP cell line 8 h after androgen withdrawal. The levels of phosphorylated ERK and CDKs decreased con-tinuously and reached the lowest after 24 h, while continuous elevation of P27kip1 was detected thereafter to 24h. No expression change of phosphorylated ERK, CDKs and P27kip1 were detected in PC-3 cell line. Conclu-sion: The androgen withdrawal can cause ERKs activation decrease and cell cycle regulation moleculeschanges, which may be one of the mechanisms for inhibited growth of androgen dependent prostate carcinomaafter androgen ablation by either operative or medicine methods.

  2. Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Eskew Jeffery D

    2011-10-01

    Full Text Available Abstract Background The molecular chaperone, heat shock protein 90 (Hsp90 has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells. Methods PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies. Results KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model. Conclusions Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.

  3. Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

    OpenAIRE

    Eskew Jeffery D; Sadikot Takrima; Morales Pedro; Duren Alicia; Dunwiddie Irene; Swink Megan; Zhang Xiaoying; Hembruff Stacey; Donnelly Alison; Rajewski Roger A; Blagg Brian SJ; Manjarrez Jacob R; Matts Robert L; Holzbeierlein Jeffrey M; Vielhauer George A

    2011-01-01

    Abstract Background The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not i...

  4. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    OpenAIRE

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen recept...

  5. Hypoxia in the androgen-dependent Shionogi model for prostate cancer at three stages.

    Science.gov (United States)

    Skov, Kirsten; Adomat, Hans; Bowden, Mary; Dragowska, Wieslawa; Gleave, Martin; Koch, Cameron J; Woo, Janet; Yapp, Donald T T

    2004-11-01

    The objective of this study was to investigate a possible relationship between androgen status and hypoxia in the Shionogi murine prostate tumor model, which is widely used to study the effects of androgen withdrawal on hormone resistance and radiation response. Binding of the nitroimidazole hypoxia marker EF5 was assessed using the Cy3-tagged monoclonal antibody ELK3-51. Three hours after injection of EF5 (30 mg/kg), tumors from the following three stages were excised: androgen-dependent, regressed tumors 7 days after castration, and androgen-independent. Half of each tumor was disaggregated for analysis by flow cytometry and the remainder was flash frozen. Statistically significant differences (P 0.1). The results from this preliminary study indicate that hypoxia may play an important role with respect to the timing of irradiation in prostate cancer treatments and possibly may be a useful prognostic tool. In addition, hypoxia may also be relevant to progression in this disease after androgen ablation. PMID:15624309

  6. Combined androgen blockade in the treatment of advanced prostate cancer--an overview. The Scandinavian Prostatic Cancer Group

    DEFF Research Database (Denmark)

    Iversen, P

    1997-01-01

    The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed.......The value of combined androgen blockade in the treatment of patients with advanced prostate cancer is still controversial. In this review by the Scandinavian Prostatic Cancer Group, the literature addressing the concept and its clinical use is critically reviewed....

  7. Abrogation of heat-shock protein (HSP)70 expression induced cell growth inhibition and apoptosis in human androgen-independent prostate cancer cell line PC-3m

    Institute of Scientific and Technical Information of China (English)

    Zhi-GangZhao; Qing-ZhengMa; Chun-XiaoXu

    2004-01-01

    Aim: To investigate the effect of abrogating heat shock protein (HSP) 70 expression by antisense HSP70 oligonucleotides treatment on human androgen-independent prostate cancer cell line PC-3m growth. Methods: PC3m cells were treated with 0-16μmol/L antisense HSP70 oligomers for 0-100 hr. Cell growth inhibition was analyzed using a trypan blue dye exclusion test. Apoptotic cells were detected and confirmed by flow cytometric analysis and DNA fragmentation analysis. The protein expression of HSP70 and bcl-2 affected by antisense HSP70 oligomers were determined using Western blot. Results: Antisense HSP70 oligomer induced apoptosis and then inhibited proliferation of PC-3m cells in a dose- and time-dependent manner. Ladder-like patterns of DNA fragments were observed in PC-3m cells treated with 10μmol/L antisense HSP70 oligomer for 48 hr or 8μtmol/L for 72 hr on agarose gel electrophoresis. Antisense HSP70 oligomer pretreatment enhanced the subsequent induction of apoptosis by heat shock in PC-3m cells. In addition, undetectable HSP70 expression was observed at a concentration of 10μtmol/L antisense HSP70 oligomer treatment for 48 hr or 8μtmol/L for 72 hr in Western blot, which was paralleled by decreased expression levels of anti-apoptotic protein bcl-2. Conclusion: HSP70 antisense oligomer treatment abro-gates the expression of HSP70, which may disrupt HSP70-bcl-2-interactions and further down-regulate bcl-2 expression,in turn inducing apoptosis and inhibiting cell growth in PC-3m cells. (Asian JAndro12004 Dec;6:319-324)

  8. Transcriptional programs activated by exposure of human prostate cancer cells to androgen

    OpenAIRE

    DePrimo, Samuel E; Diehn, Maximilian; Nelson, Joel B.; Reiter, Robert E.; Matese, John; Fero, Mike; Tibshirani, Robert; Brown, Patrick O; James D Brooks

    2002-01-01

    Background Androgens are required for both normal prostate development and prostate carcinogenesis. We used DNA microarrays, representing approximately 18,000 genes, to examine the temporal program of gene expression following treatment of the human prostate cancer cell line LNCaP with a synthetic androgen. Results We observed statistically significant changes in levels of transcripts of more than 500 genes. Many of these genes were previously reported androgen targets, but most were not prev...

  9. Beyond androgen deprivation: ancillary integrative strategies for targeting the androgen receptor addiction of prostate cancer.

    Science.gov (United States)

    McCarty, Mark F; Hejazi, Jalal; Rastmanesh, Reza

    2014-09-01

    The large majority of clinical prostate cancers remain dependent on androgen receptor (AR) activity for proliferation even as they lose their responsiveness to androgen deprivation or antagonism. AR activity can be maintained in these circumstances by increased AR synthesis--often reflecting increased NF-κB activation; upregulation of signaling pathways that promote AR activity in the absence of androgens; and by emergence of AR mutations or splice variants lacking the ligand-binding domain, which render the AR constitutively active. Drugs targeting the N-terminal transactivating domain of the AR, some of which are now in preclinical development, can be expected to inhibit the activity not only of unmutated ARs but also of the mutant forms and splice variants selected for by androgen deprivation. Concurrent measures that suppress AR synthesis or boost AR turnover could be expected to complement the efficacy of such drugs. A number of nutraceuticals that show efficacy in prostate cancer xenograft models--including polyphenols from pomegranate, grape seed, and green tea, the crucifera metabolite diindolylmethane, and the hormone melatonin--have the potential to suppress AR synthesis via downregulation of NF-κB activity; clinical doses of salicylate may have analogous efficacy. The proteasomal turnover of the AR is abetted by diets with a high ratio of long-chain omega-3 to omega-6 fatty acids, which are beneficial in prostate cancer xenograft models; berberine and sulforaphane, by inhibiting AR's interaction with its chaperone Hsp90, likewise promote AR proteasomal degradation and retard growth of human prostate cancer in nude mice. Hinge region acetylation of the AR is required for optimal transactivational activity, and low micromolar concentrations of the catechin epigallocatechin-3-gallate (EGCG) can inhibit such acetylation--possibly explaining the ability of EGCG administration to suppress androgenic activity and cell proliferation in prostate cancer

  10. Quantitative mathematical modeling of PSA dynamics of prostate cancer patients treated with intermittent androgen suppression

    Institute of Scientific and Technical Information of China (English)

    Yoshito Hirata; Koichiro Akakura; Celestia S.Higano; Nicholas Bruchovsky; Kazuyuki Aihara

    2012-01-01

    If a mathematical model is to be used in the diagnosis,treatment,or prognosis of a disease,it must describe the inherent quantitative dynamics of the state.An ideal candidate disease is prostate cancer owing to the fact that it is characterized by an excellent biomarker,prostate-specific antigen (PSA),and also by a predictable response to treatment in the form of androgen suppression therapy.Despite a high initial response rate,the cancer will often relapse to a state of androgen independence which no longer responds to manipulations of the hormonal environment.In this paper,we present relevant background information and a quantitative mathematical model that potentially can be used in the optimal management of patients to cope with biochemical relapse as indicated by a rising PSA.

  11. Hybrid optimal scheduling for intermittent androgen suppression of prostate cancer

    Science.gov (United States)

    Hirata, Yoshito; di Bernardo, Mario; Bruchovsky, Nicholas; Aihara, Kazuyuki

    2010-12-01

    We propose a method for achieving an optimal protocol of intermittent androgen suppression for the treatment of prostate cancer. Since the model that reproduces the dynamical behavior of the surrogate tumor marker, prostate specific antigen, is piecewise linear, we can obtain an analytical solution for the model. Based on this, we derive conditions for either stopping or delaying recurrent disease. The solution also provides a design principle for the most favorable schedule of treatment that minimizes the rate of expansion of the malignant cell population.

  12. Proliferative response of human prostate cancer cell to hormone inhibited by androgen receptor antisense RNA

    Institute of Scientific and Technical Information of China (English)

    江军; 王洛夫; 方玉华; 靳风烁; 靳文生

    2004-01-01

    Background The failure of endocrine treatment for advanced prostate cancer might be related to aberrant activation of androgen receptor (AR). Prostate cancer cell line LNCaP contains AR that can be activated by androgen, estrogen and progesterone. This study was set to investigate the effects of antisense AR RNA on growth of LNCaP cultured in medium containing varied concentrations of R1881, 17β-estradiol, and progesterone, respectively. Methods LNCaP cells transfected with antisense AR RNA retroviral vector pL-AR-SN were designated as LNCaPas-AR. LNCaP cells containing empty vector pLXSN served as LNCaPNeo. LNCaP and LNCaPNeo were taken as controls. In vitro cell growth assay, proliferative cells of LNCaP and tranfected LNCaPs were counted by typan staining when they cultured with synthetic androgen R1881, 17β-estradiol, and progesterone, respectively. Results Growth of LNCaPas-AR was inhibited significantly (P<0.05) compared with that of LNCaP and LNCaPNeo at 1 nmol/L R1881, 10 nmol/L 17β-estradiol, and 1 nmol/L progesterone, respectively. No difference was seen between LNCaP and LNCaPNeo(P>0.05). Microscopic observation showed that LNCaP and LNCaPNeo cells grew well, but only few LNCaPas-AR cells were alive. Conclusions Our observations indicate that antisense AR RNA retroviral vector pL-AR-SN could change androgen-independent characteristics of LNCaP cells, which might shed some novel insights into the treatment of androgen-independent prostate cancer.

  13. Wnt inhibitory factor 1 (Wif1) is regulated by androgens and enhances androgen-dependent prostate development.

    Science.gov (United States)

    Keil, Kimberly P; Mehta, Vatsal; Branam, Amanda M; Abler, Lisa L; Buresh-Stiemke, Rita A; Joshi, Pinak S; Schmitz, Christopher T; Marker, Paul C; Vezina, Chad M

    2012-12-01

    Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-responsive steroid 5α-reductase 2 (Srd5a2). Wif1 mRNA is also present in prostatic buds during their elongation and branching morphogenesis. Androgens are necessary and sufficient for Wif1 expression in mouse UGS explant mesenchyme, and testicular androgens remain necessary for normal Wif1 expression in adult mouse prostate stroma. WIF1 contributes functionally to prostatic bud formation. In the presence of androgens, exogenous WIF1 protein increases prostatic bud number and UGS basal epithelial cell proliferation without noticeably altering the pattern of WNT/β-catenin-responsive Axin2 or lymphoid enhancer binding factor 1 (Lef1) mRNA. Wif1 mutant male UGSs exhibit increased (Sfrp)2 and (Sfrp)3 expression and form the same number of prostatic buds as the wild-type control males. Collectively our results reveal Wif1 as one of the few known androgen-responsive genes in the fetal mouse UGM and support the hypothesis that androgen-dependent Wif1 expression is linked to the mechanism of androgen-induced prostatic bud formation.

  14. Targeting Androgen Receptor Aberrations in Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Sharp, Adam; Welti, Jonathan; Blagg, Julian; de Bono, Johann S

    2016-09-01

    Androgen receptor (AR) splice variants (SV) have been implicated in the development of metastatic castration-resistant prostate cancer and resistance to AR targeting therapies, including abiraterone and enzalutamide. Agents targeting AR-SV are urgently needed to test this hypothesis and further improve the outcome of patients suffering from this lethal disease. Clin Cancer Res; 22(17); 4280-2. ©2016 AACRSee related article by Yang et al., p. 4466.

  15. The androgen receptor in hormone-refractory prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hai-Lei Mao; Zhi-Qi Zhu; Charlie Degui Chen

    2009-01-01

    Advanced prostate cancer is responsive to hormone therapy that interferes with androgen receptor (AR) signalling.However,the effect is short-lived,as nearly all tumours progress to a hormone-refractory (HR) state,a lethal stage of the disease.Intuitively,the AR should not be involved because hormone therapy that blocks or reduces AR activity is not effective in treating HR turnouts.However,there is still a consensus that AR plays an essential role in HR prostate cancer (HRPC) because AR signalling is still functional in HR tumours.AR signalling can be activated in HR turnouts through several mechanisms.First,activation of intracellular signal transduction pathways can sensitize the AR to castrate levels of androgens.Also,mutations in the AR can change AR ligand specificity,thereby allowing it to be activated by non-steroids or anti-androgens.Finally,overexpression of the wild-type AR sensitizes itself to low concentrations of androgens.Therefore,drugs targeting AR signalling could still be effective in treating HRPC.

  16. Androgen receptor is the key transcriptional mediator of the tumor suppressor SPOP in prostate cancer.

    Science.gov (United States)

    Geng, Chuandong; Rajapakshe, Kimal; Shah, Shrijal S; Shou, John; Eedunuri, Vijay Kumar; Foley, Christopher; Fiskus, Warren; Rajendran, Mahitha; Chew, Sue Anne; Zimmermann, Martin; Bond, Richard; He, Bin; Coarfa, Cristian; Mitsiades, Nicholas

    2014-10-01

    Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas, but are rare in other malignancies, suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator SRC-3. However, the relative contributions that SPOP substrates may make to the pathophysiology of SPOP-mutant (mt) prostate adenocarcinomas are unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of prostate adenocarcinoma cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger similarity to AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR-mediated. Indeed, we found that wild-type (wt) but not prostate adenocarcinoma-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of prostate adenocarcinoma cells expressing mt-SPOP exhibited higher AR protein levels and grew faster than tumors composed of prostate adenocarcinoma cells expressing wt-SPOP. Furthermore, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human prostate adenocarcinoma datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in prostate adenocarcinoma and provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.

  17. Androgen mediated translational and postranslational regulation of IGFBP-2 in androgen-sensitive LNCaP human prostate cancer cells

    OpenAIRE

    David J. DeGraff; Aguiar, Adam A.; Chen, Qian; Adams, Lisa K.; Williams, B. Jill; Sikes, Robert A.

    2010-01-01

    The insulin-like growth factor (IGF) axis is associated intimately with prostate cancer (PCa) development, growth, survival and metastasis. In particular, increased levels of IGFBP-2 expression are associated with advanced PCa, bone metastasis, and the development of castrate resistant PCa. Previously, we reported that androgen treatment decreased intracellular and extracellular IGFBP-2 in the androgen sensitive (AS) PCa cell line, LNCaP. Nonetheless, the mechanism by which androgen treatment...

  18. Effects of androgen receptor and androgen on gene expression in prostate stromal fibroblasts and paracrine signaling to prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Matthew J Tanner

    Full Text Available The androgen receptor (AR is expressed in a subset of prostate stromal cells and functional stromal cell AR is required for normal prostate developmental and influences the growth of prostate tumors. Although we are broadly aware of the specifics of the genomic actions of AR in prostate cancer cells, relatively little is known regarding the gene targets of functional AR in prostate stromal cells. Here, we describe a novel human prostate stromal cell model that enabled us to study the effects of AR on gene expression in these cells. The model involves a genetically manipulated variant of immortalized human WPMY-1 prostate stromal cells that overexpresses wildtype AR (WPMY-AR at a level comparable to LNCaP cells and is responsive to dihydrotestosterone (DHT stimulation. Use of WPMY-AR cells for gene expression profiling showed that the presence of AR, even in the absence of DHT, significantly altered the gene expression pattern of the cells compared to control (WPMY-Vec cells. Treatment of WPMY-AR cells, but not WPMY-Vec control cells, with DHT resulted in further changes that affected the expression of 141 genes by 2-fold or greater compared to vehicle treated WPMY-AR cells. Remarkably, DHT significantly downregulated more genes than were upregulated but many of these changes reversed the initial effects of AR overexpression alone on individual genes. The genes most highly effected by DHT treatment were categorized based upon their role in cancer pathways or in cell signaling pathways (transforming growth factor-β, Wnt, Hedgehog and MAP Kinase thought to be involved in stromal-epithelial crosstalk during prostate or prostate cancer development. DHT treatment of WPMY-AR cells was also sufficient to alter their paracrine potential for prostate cancer cells as conditioned medium from DHT-treated WPMY-AR significantly increased growth of LNCaP cells compared to DHT-treated WPMY-Vec cell conditioned medium.

  19. To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy

    International Nuclear Information System (INIS)

    Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge

  20. Androgen receptor isoforms in human and rat prostate

    Institute of Scientific and Technical Information of China (English)

    Shu-JieXIA; Gang-YaoHAO; Xiao-DaTANG

    2000-01-01

    Aim: To investigate the androgen receptor (AR) isoforms and its variability of expression in human and rat prostatic tissues. Methods: Human benign prostatic hyperplasia (BPH) and prostatic cancer tissues were obtained from patients undergoing prostatectomy, and rat ventral prostate was incised 3 days after castration. Forty-one AR-positive BPH specimens, 3 prostatic cancer specimens, and 6 rat prostates were used. After processing at 4℃, the tissues were examined by means of high resolution isoelectric focusing (IEF) technique to determine their AR isoforms. Results:From the prostatic specimens, 3 types of AR isoforms were detected with pI values at 6.5, 6.0, and 5.3. In human BPH tissues, 15/41 (36.6%) specimens showed all the three types of isoforms, while 19/41 (46.3%) showed 2 isoforms at various combinations and 7/41(17.1%), 1 isoform. For the 3 prostatic cancer specimens, one showed 3 isoforms, one, 2 isoforms, and the other failed to show any isoform. All rat prostatic tissues showed 2 isoforms at different combinations. Binding of 3H-dihydrotestosterone (DHT) to the isoforms was inhibited by the addition of 100-fold excess of DHT or testosterone, but not progesterone, oestradiol or diethylstilboestrol. Conclusion: AR isoforms are different in different patients. Although their genesis is not clear, the therapeutic implication of the present observation appears to be interesting, that may help clarifying the individual differences in the response to hormonal therapy.(Asian J Androl 2000 Dec;2:307-310)

  1. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

    Directory of Open Access Journals (Sweden)

    John M Kokontis

    Full Text Available The majority of prostate cancer (PCa patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC. We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1; and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1 and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  2. Androgen suppresses the proliferation of androgen receptor-positive castration-resistant prostate cancer cells via inhibition of Cdk2, CyclinA, and Skp2.

    Science.gov (United States)

    Kokontis, John M; Lin, Hui-Ping; Jiang, Shih Sheng; Lin, Ching-Yu; Fukuchi, Junichi; Hiipakka, Richard A; Chung, Chi-Jung; Chan, Tzu-Min; Liao, Shutsung; Chang, Chung-Ho; Chuu, Chih-Pin

    2014-01-01

    The majority of prostate cancer (PCa) patient receiving androgen ablation therapy eventually develop castration-resistant prostate cancer (CRPC). We previously reported that androgen treatment suppresses Skp2 and c-Myc through androgen receptor (AR) and induced G1 cell cycle arrest in androgen-independent LNCaP 104-R2 cells, a late stage CRPC cell line model. However, the mechanism of androgenic regulation of Skp2 in CRPC cells was not fully understood. In this study, we investigated the androgenic regulation of Skp2 in two AR-positive CRPC cell line models, the LNCaP 104-R1 and PC-3AR Cells. The former one is an early stage androgen-independent LNCaP cells, while the later one is PC-3 cells re-expressing either wild type AR or mutant LNCaP AR. Proliferation of LNCaP 104-R1 and PC-3AR cells is not dependent on but is suppressed by androgen. We observed in this study that androgen treatment reduced protein expression of Cdk2, Cdk7, Cyclin A, cyclin H, Skp2, c-Myc, and E2F-1; lessened phosphorylation of Thr14, Tyr15, and Thr160 on Cdk2; decreased activity of Cdk2; induced protein level of p27(Kip1); and caused G1 cell cycle arrest in LNCaP 104-R1 cells and PC-3AR cells. Overexpression of Skp2 protein in LNCaP 104-R1 or PC-3AR cells partially blocked accumulation of p27(Kip1) and increased Cdk2 activity under androgen treatment, which partially blocked the androgenic suppressive effects on proliferation and cell cycle. Analyzing on-line gene array data of 214 normal and PCa samples indicated that gene expression of Skp2, Cdk2, and cyclin A positively correlates to each other, while Cdk7 negatively correlates to these genes. These observations suggested that androgen suppresses the proliferation of CRPC cells partially through inhibition of Cyclin A, Cdk2, and Skp2.

  3. Neoadjuvant androgen withdrawal prior to external radiotherapy for locally advanced adenocarcinoma of the prostate

    International Nuclear Information System (INIS)

    It is unclear whether positive interactions between radiation and androgen withdrawal for patients with locally advanced prostate cancer is synergistic or additive. The present study aimed to clarify the significance of neoadjuvant androgen ablation prior to external radiotherapy in a human prostate LNCaP tumor model and in patients with locally advanced prostate cancer. Comparisons were made between the effect of castration prior to radiation on the growth of subcutaneous LNCaP tumors implanted into male nude mice and their serum prostate-specific antigen (PSA) levels, and the results of castration or radiation alone. Twenty-nine patients with histologically proven and locally advanced adenocarcinoma of the prostate were treated with luteinizing hormone-releasing hormone analog at least 3 months before, during, and after external radiation therapy with a total dose of 70 Gy. The toxicity and response to this therapy were evaluated. Treatment combining castration and radiation resulted in synergistic inhibition of LNCaP tumor growth and a significant delay in the emergence of androgen-independent recurrence as opposed to either treatment alone. The external radiotherapy was completed in 28 patients (96.6%), resulting in a reduction of serum PSA levels in all 28 patients to below 1.0 ng/mL. All patients were alive after a mean follow-up period of 34 months (range 11-53) with a 3-year PSA relapse-free survival rate of 83.7%. Among several factors examined, only the Gleason score was significantly associated with PSA relapse-free survival in univariate analysis, but not in multivariate analysis. Thirteen of 28 patients (46%) and 7 of 28 (25%) also showed at least one form of gastrointestinal or genitourinary toxicity, respectively. Of these patients, 8 with gastrointestinal toxicities, and 1 with genitourinary toxicity, experienced acute complications higher than grade 3. The experimental findings objectively suggested the use of neoadjuvant androgen withdrawal prior

  4. Oriental herbs as a source of novel anti-androgen and prostate cancer chemopreventive agents

    Institute of Scientific and Technical Information of China (English)

    Junxuan L(U); Sung-Hoon KIM; Cheng JIANG; HyoJeong LEE; Junming GUO

    2007-01-01

    Androgen and androgen receptor (AR) signaling are crucial for the genesis of prostate cancer (Pca), which can often develop into androgen-ligand-indepen-dent diseases that are lethal to the patients. Recent studies show that even these hormone-refractory Pca require ligand-independent AR signaling for survival. As current chemotherapy is largely ineffective for Pca and has serious toxic side-effects, we have initiated a collaborative effort to identify and develop novel, safe and naturally occurring agents that target AR signaling from Oriental medicinal herbs for the chemoprevention and treatment of Pca. We highlight our discovery of decursin from an Oriental formula containing Korean Angelica gigas Nakal(Dang Gui) root as a novel anti-androgen/AR agent. We have identified the following mechanisms to account for the specific anti-AR actions: rapid block of AR nuclear translocation, inhibition of binding of 5α-dihydrotestesterone to Arand increased proteasomal degradation of AR protein. Furthermore, decursin lacks the agonist activity of the "pure" anti-androgen bicalutamide and is more potent than bicalutamide in inducing Pca apoptosis. Structure-activity analyses reveal a critical requirement of the side-chain on decursin or its structural isomerdecursinol angelate for anti-AR, cell cycle arrest and proapoptotic activities. This work demonstrates the feasibility of using activity-guided fractionation in cell culture assays combined with mechanistic studies to identify novel anti-andro-gen/AR agents from complex herbal mixtures.

  5. Androgens regulate Hedgehog signalling and proliferation in androgen-dependent prostate cells.

    Science.gov (United States)

    Sirab, Nanor; Terry, Stéphane; Giton, Frank; Caradec, Josselin; Chimingqi, Mihelaiti; Moutereau, Stéphane; Vacherot, Francis; de la Taille, Alexandre; Kouyoumdjian, Jean-Claude; Loric, Sylvain

    2012-09-15

    Prostate cancer (PCa) is androgen sensitive in its development and progression to metastatic disease. Hedgehog (Hh) pathway activation is important in the initiation and growth of various carcinomas including PCa. We and others have observed aberrations of Hh pathway during the progression of PCa to the castration-resistant state. The involvement of androgen signalling in Hh pathway activation, however, remains largely elusive. Here we investigate the direct role of androgen signalling on Hh pathway. We examined the effect of Dihydrosterone (DHT), antiandrogen, bicalutamide, and Hh pathway inhibitor, KAAD-cyclopamine in four human prostate cell lines (two cancerous: LNCaP, VCaP, and two normal: PNT2 and PNT2-ARm which harbours a mutant version of androgen receptor (AR) that is commonly found in LNCaP). Cell proliferation as well as Hh pathway members (SHH, IHH, DHH, GLI, PTCH) mRNA expression levels were assessed. We showed that KAAD-cyclopamine decreased cell proliferation of DHT-stimulated LNCaP, VCaP and PNT2-ARm cells. SHH expression was found to be downregulated by DHT in all AR posititve cells. The negative effect of DHT on SHH expression was counteracted when cells were treated by bicalutamide. Importantly, KAAD-cyclopamine treatment seemed to inhibit AR activity. Moreover, bicalutamide as well as KAAD-cyclopamine treatments induced GLI and PTCH expression in VCaP and PNT2-ARm. Our results suggest that Hh pathway activity can be regulated by androgen signalling. Specifically, we show that the DHT-induced inhibition of Hh pathway is AR dependent. The mutual interaction between these two pathways might be important in the regulation of cell proliferation in PCa.

  6. Angiogenin mediates androgen-stimulated growth of prostate cancer cells and correlates with castration resistance

    OpenAIRE

    Li, Shuping; Hu, Miaofen G.; Sun, Yeqing; YOSHIOKA, NORIE; IBARAGI, SOICHIRO; Sheng, Jinghao; Sun, Guangjie; Kishimoto, Koji; Hu, Guo-fu

    2013-01-01

    Androgen receptor (AR) is a critical effector of prostate cancer (PCa) development and progression. Androgen-dependent PCa rely on the function of AR for growth and progression. Many castration-resistant PCa continue to depend on AR signaling for survival and growth. Ribosomal RNA (rRNA) is essential for both androgen-dependent and castration-resistant growth of PCa cells. During androgen-dependent growth of prostate cells, androgen-AR signaling leads to the accumulation of rRNA. However, the...

  7. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

    Science.gov (United States)

    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-01

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention.

  8. A nonlinear competitive model of the prostate tumor growth under intermittent androgen suppression.

    Science.gov (United States)

    Yang, Jing; Zhao, Tong-Jun; Yuan, Chang-Qing; Xie, Jing-Hui; Hao, Fang-Fang

    2016-09-01

    Hormone suppression has been the primary modality of treatment for prostate cancer. However long-term androgen deprivation may induce androgen-independent (AI) recurrence. Intermittent androgen suppression (IAS) is a potential way to delay or avoid the AI relapse. Mathematical models of tumor growth and treatment are simple while they are capable of capturing the essence of complicated interactions. Game theory models have analyzed that tumor cells can enhance their fitness by adopting genetically determined survival strategies. In this paper, we consider the survival strategies as the competitive advantage of tumor cells and propose a new model to mimic the prostate tumor growth in IAS therapy. Then we investigate the competition effect in tumor development by numerical simulations. The results indicate that successfully IAS-controlled states can be achieved even though the net growth rate of AI cells is positive for any androgen level. There is crucial difference between the previous models and the new one in the phase diagram of successful and unsuccessful tumor control by IAS administration, which means that the suggestions from the models for medication can be different. Furthermore we introduce quadratic logistic terms to the competition model to simulate the tumor growth in the environment with a finite carrying capacity considering the nutrients or inhibitors. The simulations show that the tumor growth can reach an equilibrium state or an oscillatory state with the net growth rate of AI cells being androgen independent. Our results suggest that the competition and the restraint of a limited environment can enhance the possibility of relapse prevention. PMID:27259386

  9. Origin of Androgen-Insensitive Poorly Differentiated Tumors in the Transgenic Adenocarcinoma of Mouse Prostate Model

    Directory of Open Access Journals (Sweden)

    Wendy J. Huss

    2007-11-01

    Full Text Available Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR. Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag-expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.

  10. Is there a relationship between androgenic alopecia and benign prostatic hyperplasia?

    OpenAIRE

    Ladan Dastgheib; Mehdi Shirazi; Iman Moezzi; Saber Dehghan; Maryam-Sadat Sadati

    2015-01-01

    Androgenic alopecia as a physiologic process and benign prostatic hyperplasia (BPH) as a pathologic process in the older population are androgen-dependent processes influenced by 5-alpha reductase enzyme which converts testosterone to dihydrotestosterone. This cross sectional study was done to evaluate the relationship between androgenic alopecia and BPH. 150 men older than 50 years old, who presented to the free prostate screening clinic, were included. They were asked about urinary symptoms...

  11. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

    OpenAIRE

    Rennie, Paul S.; Artem Cherkasov; Nada Lallous; Kush Dalal

    2013-01-01

    Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR) is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the ...

  12. 多西他赛联合沙利度胺治疗激素非依赖性晚期前列腺癌的临床观察%Clinical research on treatment of advanced androgen independent prostate cancer with Docetaxel and Thalidomide

    Institute of Scientific and Technical Information of China (English)

    Jing Tian; Donghai Teng; Xiangdong Shu; Hong Lu; Hui Chen; Peng Guo

    2009-01-01

    Objective:To evaluate the clinical effects and adverse reactions of Docetaxel and Thalidomide in treating ad-vanced androgen independent prostate cancer (AIPC). Methods:12 cases of advanced AIPC were given a combined treat-ment of Docataxel and Thalidomide, with Docetaxel 75 mg/m2 on day 1 and Thalidomide 100 mg per day as initial dose and 300 mg as terminal dose by an increase of 50 mg every week. Results:The post-treatment values of prostate specific antigen (PSA) were normal (< 4 ng/L) in 10 patients, less than 50% of pretreatment value in one patient, and no significant change in one patient. The median survival time was 14 months and period of the median symptoms reduction was 16.3 months. Com-mon adverse reactions were tolerable, including nausea, vomiting, leukopenia, anemia and thrombocytopenia. Conclusion:The regimen of Docetaxel combined with Thalidomide was effective and tolerable in the treatment of advanced AIPC.

  13. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Sheng-Qiang Yu; Kuo-Pao Lai; Shu-Jie Xia; Hong-Chiang Chang; Chawnshang Chang; Shuyuan Yeh

    2009-01-01

    The androgen receptor (AR) plays an important role in the development and progression of prostate cancer (PCa).Androgen deprivation therapy is initially effective in blocking tumor growth,but it eventually leads to the hormonerefractory state.The detailed mechanisms of the conversion from androgen dependence to androgen independence remain unclear.Several PCa cell lines were established to study the role of AR in PCa,but the results were often inconsistent or contrasting in different cell lines,or in the same cell line grown under different conditions.The cellular and molecular alteration of epithelial cells and their microenvironments are complicated,and it is difficult to use a single cell line to address this important issue and also to study the pathophysiological effects of AR.In this paper,we summarize the different effects of AR on multiple cell lines and show the disadvantages of using a single human PCa cell line to study AR effects on PCa.We also discuss the advantages of widely used epithelium-stroma co-culture systems,xenograft mouse models,and genetically engineered PCa mouse models.The combination of in vitro cell line studies and in vivo mouse models might lead to more credible results and better strategies for the study of AR roles in PCa.

  14. Phosphorylation of the androgen receptor by PIM1 in hormone refractory prostate cancer.

    Science.gov (United States)

    Ha, S; Iqbal, N J; Mita, P; Ruoff, R; Gerald, W L; Lepor, H; Taneja, S S; Lee, P; Melamed, J; Garabedian, M J; Logan, S K

    2013-08-22

    Integration of cellular signaling pathways with androgen receptor (AR) signaling can be achieved through phosphorylation of AR by cellular kinases. However, the kinases responsible for phosphorylating the AR at numerous sites and the functional consequences of AR phosphorylation are only partially understood. Bioinformatic analysis revealed AR serine 213 (S213) as a putative substrate for PIM1, a kinase overexpressed in prostate cancer. Therefore, phosphorylation of AR serine 213 by PIM1 was examined using a phosphorylation site-specific antibody. Wild-type PIM1, but not catalytically inactive PIM1, specifically phosphorylated AR but not an AR serine-to-alanine mutant (S213A). In vitro kinase assays confirmed that PIM1 can phosphorylate AR S213 in a ligand-independent manner and cell type-specific phosphorylation was observed in prostate cancer cell lines. Upon PIM1 overexpression, AR phosphorylation was observed in the absence of hormone and was further increased in the presence of hormone in LNCaP, LNCaP-abl and VCaP cells. Moreover, phosphorylation of AR was reduced in the presence of PIM kinase inhibitors. An examination of AR-mediated transcription showed that reporter gene activity was reduced in the presence of PIM1 and wild-type AR, but not S213A mutant AR. Androgen-mediated transcription of endogenous PSA, Nkx3.1 and IGFBP5 was also decreased in the presence of PIM1, whereas IL6, cyclin A1 and caveolin 2 were increased. Immunohistochemical analysis of prostate cancer tissue microarrays showed significant P-AR S213 expression that was associated with hormone refractory prostate cancers, likely identifying cells with catalytically active PIM1. In addition, prostate cancers expressing a high level of P-AR S213 were twice as likely to be from biochemically recurrent cancers. Thus, AR phosphorylation by PIM1 at S213 impacts gene transcription and is highly prevalent in aggressive prostate cancer.

  15. Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

    Science.gov (United States)

    Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

    2016-07-22

    It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. PMID:27179779

  16. Androgen receptor functioned as a suppressor in the prostate cancer cell line PC3 in vitro and in vivo

    Institute of Scientific and Technical Information of China (English)

    YU Sheng-qiang; HAN Bang-min; SHAO Yi; WU Ji-tao; ZHAO Fu-jun; LIU Hai-tao; SUN Xiao-wen; TANG Yue-qing; XIA Shu-jie

    2009-01-01

    Background Prostate cancer is one of the most common urogenital tumors in the world with an increasing incidence in China. Androgen deprivation therapy is the major therapeutic option for advanced prostate cancer. However, the role of androgen receptor (AR) in hormone-refractory prostate cancer still remains unclear. This work aimed to investigate the role of AR in an androgen independent prostate cancer cell line by in vitro and in vivo studies.Methods The role of AR in the proliferation and invasion/metastasis ability of PC3-AR9 (a PC3 stable clone expressing human AR driven by natural human AR promoter) were examined with MTT assay, soft agar assay, chamber invasion assay, wound healing assay, and also with orthotopic xenograft mouse model.Results Restoring androgen receptor in PC3 cells resulted in decreased proliferation and invasion/metastasis ability in MTT, soft agar, chamber invasion and wound healing assay. In the mouse orthotopic xenograft model, PC3-AR9 resulted in smaller primary tumors and metastasis tumors, with a lower proliferation rate and higher apoptosis rate.Conclusion The AR might function as a tumor suppressor in PC3 cells both in vitro and in vivo.

  17. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

    Directory of Open Access Journals (Sweden)

    Abeer M Mahmoud

    Full Text Available Blocking the androgen receptor (AR activity is the main goal of therapies for advanced prostate cancer (PCa. However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  18. Differential effects of genistein on prostate cancer cells depend on mutational status of the androgen receptor.

    Science.gov (United States)

    Mahmoud, Abeer M; Zhu, Tian; Parray, Aijaz; Siddique, Hifzur R; Yang, Wancai; Saleem, Mohammad; Bosland, Maarten C

    2013-01-01

    Blocking the androgen receptor (AR) activity is the main goal of therapies for advanced prostate cancer (PCa). However, relapse with a more aggressive, hormone refractory PCa arises, which harbors restored AR activity. One mechanism of such reactivation occurs through acquisition of AR mutations that enable its activation by various steroidal and non-steroidal structures. Thus, natural and chemical compounds that contribute to inappropriate (androgen-independent) activation of the AR become an area of intensive research. Here, we demonstrate that genistein, a soy phytoestrogen binds to both the wild and the Thr877Ala (T877A) mutant types of AR competitively with androgen, nevertheless, it exerts a pleiotropic effect on PCa cell proliferation and AR activity depending on the mutational status of the AR. Genistein inhibited, in a dose-dependent way, cell proliferation and AR nuclear localization and expression in LAPC-4 cells that have wild AR. However, in LNCaP cells that express the T877A mutant AR, genistein induced a biphasic effect where physiological doses (0.5-5 µmol/L) stimulated cell growth and increased AR expression and transcriptional activity, and higher doses induced inhibitory effects. Similar biphasic results were achieved in PC-3 cells transfected with AR mutants; T877A, W741C and H874Y. These findings suggest that genistein, at physiological concentrations, potentially act as an agonist and activate the mutant AR that can be present in advanced PCa after androgen ablation therapy.

  19. Myoglobin expression in prostate cancer is correlated to androgen receptor expression and markers of tumor hypoxia.

    Science.gov (United States)

    Meller, Sebastian; Bicker, Anne; Montani, Matteo; Ikenberg, Kristian; Rostamzadeh, Babak; Sailer, Verena; Wild, Peter; Dietrich, Dimo; Uhl, Barbara; Sulser, Tullio; Moch, Holger; Gorr, Thomas A; Stephan, Carsten; Jung, Klaus; Hankeln, Thomas; Kristiansen, Glen

    2014-10-01

    Recent studies identified unexpected expression and transcriptional complexity of the hemoprotein myoglobin (MB) in human breast cancer but its role in prostate cancer is still unclear. Expression of MB was immunohistochemically analyzed in three independent cohorts of radical prostatectomy specimens (n = 409, n = 625, and n = 237). MB expression data were correlated with clinicopathological parameters and molecular parameters of androgen and hypoxia signaling. Expression levels of novel tumor-associated MB transcript variants and the VEGF gene as a hypoxia marker were analyzed using qRT-PCR. Fifty-three percent of the prostate cancer cases were MB positive and significantly correlated with androgen receptor (AR) expression (p < 0.001). The positive correlation with CAIX (p < 0.001) and FASN (p = 0.008) as well as the paralleled increased expression of the tumor-associated MB transcript variants and VEGF suggest that hypoxia participates in MB expression regulation. Analogous to breast cancer, MB expression in prostate cancer is associated with steroid hormone signaling and markers of hypoxia. Further studies must elucidate the novel functional roles of MB in human carcinomas, which probably extend beyond its classic intramuscular function in oxygen storage. PMID:25172328

  20. Impact of pre-treatment prostate tissue androgen content on the prediction of castration-resistant prostate cancer development in patients treated with primary androgen deprivation therapy.

    Science.gov (United States)

    Shibata, Y; Suzuki, K; Arai, S; Miyoshi, Y; Umemoto, S; Masumori, N; Kamiya, N; Ichikawa, T; Kitagawa, Y; Mizokami, A; Sugimura, Y; Nonomura, N; Sakai, H; Honma, S; Kubota, Y

    2013-05-01

    Great advances in tissue androgen analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) have made it possible to evaluate the tissue androgen content from a single needle prostate biopsy specimen. In this study, we investigated if pre-treatment androgen content in prostate biopsy specimens could predict their response to primary androgen deprivation therapy (ADT) and future castration-resistant prostate cancer (CRPC). One-hundred and sixty-five prostate cancer patients who received primary ADT were enrolled. They had received multiple core prostate needle biopsy at diagnosis, and an additional one needle biopsy specimen was obtained for tissue androgen determination using LC-MS/MS. The patients' prostate specific antigen (PSA) values were periodically followed during the treatment and patients were determined to have CRPC when their PSA value increased continuously to 25% above the nadir and a 2.0 ng/mL increase. A significant correlation was found between PSA value decline velocity (PSA half-time) after ADT and pre-ADT tissue androgen content. Twenty-three patients were determined to have CRPC. These CRPC patients had a significantly high concentration of tissue T (p development. By using the two statistically significant variables, the relative risk of CRPC development could be calculated. The results of this study suggest that the evaluation of prostate androgen content in a single needle biopsy specimen may be useful to predict future CRPC development after primary ADT. Further studies are required for the clinical application of T/DHT ratio evaluation. PMID:23444052

  1. Specific interaction of radioactive anti-androgen TSAA-291 with androgen receptor in rat prostates

    International Nuclear Information System (INIS)

    A steroidal anti-androgen TSSA-291 (16β-ethyl-17β-hydroxy-4-oestren-3-one) bound to a macromolecular component in the cytosol of rat ventral prostates with high affinity (Kdsub(d) = 5.0 x 10-9M) and in a saturable manner. The number of binding sites was comparable to that for 5α-dihydrotestosterone (5α-DHT). [3H]TSAA-291 binding was effectively displaced by unlabelled 5α-DHT, 19-nortestosterone and cyproterone acetate but to a lesser degree by corticosterone. Glycerol density-gradient centrifugation analysis revealed that the sedimentation coefficient of the [3H]-TSAA-291-macromolecule complex was 3-4.5 S. However, when the unlabelled cytosol was fractionated by glycerol density-gradient centrifugation before the binding of [3H]TSAA-291 was examined, specific binding of [3H]TSAA-291 was observed in fractions corresponding to 8-10 S. Binding of the [3H]TSAA-291-macromolecules comples to prostatic nuclei and DNA-cellulose was considerably less than binding by the [3H]5α-DHT-macromolecule complex. Instability of the TSAA-291 binding coponent on heat treatment before and after complex formation was also revealed and the results are discussed in terms of the anti-androgenic activity of TSAA-291. (author)

  2. Effects of low testosterone levels and of adrenal androgens on growth of prostate tumor models in nude mice

    NARCIS (Netherlands)

    W.M. van Weerden (Wytske); G.J. van Steenbrugge (Gert Jan); A. van Kreuningen (A.); E.P.C.M. Moerings (Ellis); F.H. de Jong (Frank); F.H. Schröder (Fritz)

    1990-01-01

    markdownabstractAbstract Two transplantable, androgen dependent prostate tumor models of human origin, PC-82 and PC-EW, were used to study the effect of low androgen levels and adrenal androgens on prostate tumor cell proliferation. Tumor load of the PC-82 and PC-EW tumors could be maintained cons

  3. Androgen receptor targeted therapies in castration-resistant prostate cancer: Bench to clinic.

    Science.gov (United States)

    Imamura, Yusuke; Sadar, Marianne D

    2016-08-01

    The androgen receptor is a transcription factor and validated therapeutic target for prostate cancer. Androgen deprivation therapy remains the gold standard treatment, but it is not curative, and eventually the disease will return as lethal castration-resistant prostate cancer. There have been improvements in the therapeutic landscape with new agents approved, such as abiraterone acetate, enzalutamide, sipuleucel-T, cabazitaxel and Ra-223, in the past 5 years. New insight into the mechanisms of resistance to treatments in advanced disease is being and has been elucidated. All current androgen receptor-targeting therapies inhibit the growth of prostate cancer by blocking the ligand-binding domain, where androgen binds to activate the receptor. Persuasive evidence supports the concept that constitutively active androgen receptor splice variants lacking the ligand-binding domain are one of the resistant mechanisms underlying advanced disease. Transcriptional activity of the androgen receptor requires a functional AF-1 region in its N-terminal domain. Preclinical evidence proved that this domain is a druggable target to forecast a potential paradigm shift in the management of advanced prostate cancer. This review presents an overview of androgen receptor-related mechanisms of resistance as well as novel therapeutic agents to overcome resistance that is linked to the expression of androgen receptor splice variants in castration-resistant prostate cancer. PMID:27302572

  4. Perinatal exposure to mixtures of anti-androgenic chemicals causes proliferative lesions in rat prostate

    DEFF Research Database (Denmark)

    Boberg, Julie; Johansson, Hanna Katarina Lilith; Hadrup, Niels;

    2015-01-01

    BACKGROUND: Elevated levels of endogenous or exogenous estrogens during fetal life can induce permanent disturbances in prostate growth and predispose to precancerous lesions. Recent studies have indicated that also early anti-androgen exposure may affect prostate cancer risk. METHODS: We examined...... disrupters relevant for human exposure was found to elicit persistent effects on the rat prostate following perinatal exposure, suggesting that human perinatal exposure to environmental chemicals may increase the risk of prostate cancer later in life. Prostate....... the influence of perinatal exposure to mixtures of anti-androgenic and estrogenic chemicals on prostate development. Wistar rats were exposed from gestation day 7 to postnatal day 22 to a mixture of 8 anti-androgenic compounds (AAMix), a mixture of four estrogenic compounds (EMix), or paracetamol or a mixture...

  5. Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer.

    Science.gov (United States)

    McGrath, Meagan J; Binge, Lauren C; Sriratana, Absorn; Wang, Hong; Robinson, Paul A; Pook, David; Fedele, Clare G; Brown, Susan; Dyson, Jennifer M; Cottle, Denny L; Cowling, Belinda S; Niranjan, Birunthi; Risbridger, Gail P; Mitchell, Christina A

    2013-08-15

    It is now clear that progression from localized prostate cancer to incurable castrate-resistant prostate cancer (CRPC) is driven by continued androgen receptor (AR), signaling independently of androgen. Thus, there remains a strong rationale to suppress AR activity as the single most important therapeutic goal in CRPC treatment. Although the expression of ligand-independent AR splice variants confers resistance to AR-targeted therapy and progression to lethal castrate-resistant cancer, the molecular regulators of AR activity in CRPC remain unclear, in particular those pathways that potentiate the function of mutant AR in CRPC. Here, we identify FHL2 as a novel coactivator of ligand-independent AR variants that are important in CRPC. We show that the nuclear localization of FHL2 and coactivation of the AR is driven by calpain cleavage of the cytoskeletal protein filamin, a pathway that shows differential activation in prostate epithelial versus prostate cancer cell lines. We further identify a novel FHL2-AR-filamin transcription complex, revealing how deregulation of this axis promotes the constitutive, ligand-independent activation of AR variants, which are present in CRPC. Critically, the calpain-cleaved filamin fragment and FHL2 are present in the nucleus only in CRPC and not benign prostate tissue or localized prostate cancer. Thus, our work provides mechanistic insight into the enhanced AR activation, most notably of the recently identified AR variants, including AR-V7 that drives CRPC progression. Furthermore, our results identify the first disease-specific mechanism for deregulation of FHL2 nuclear localization during cancer progression. These results offer general import beyond prostate cancer, given that nuclear FHL2 is characteristic of other human cancers where oncogenic transcription factors that drive disease are activated like the AR in prostate cancer.

  6. Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Rosenberg JE

    2012-01-01

    Full Text Available Yasser Rehman1, Jonathan E Rosenberg21Division of Hospital Medicine, UMass Memorial Healthcare, Worcester, MA, USA; 2Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Prostate cancer is the second leading cause of cancer death in men in the US and Europe. The treatment of advanced-stage prostate cancer has been androgen deprivation. Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes, but adrenal glands and even prostate cancer tissue continue to produce androgens, which eventually leads to continued prostate cancer growth despite castrate level of androgens. This stage is known as castrate-resistant prostate cancer (CRPC, which continues to be a challenge to treat. Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate-specific antigen levels further, but has not actually translated into life-prolonging options. The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer. Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting. One such agent is abiraterone acetate, which significantly reduces androgen production by blocking the enzyme, cytochrome P450 17 alpha-hydroxylase (CYP17. This has provided physicians with another treatment option for patients with CRPC. The landscape for prostate cancer treatment has changed with the approval of cabazitaxel, sipuleucel-T and abiraterone. Here we provide an overview of abiraterone acetate, its mechanism of action, and its potential place for therapy in CRPC.Keywords: CRPC, abiraterone, CYP17, inhibitors, androgens, castration resistant prostate cancer

  7. Glycogen synthesis correlates with androgen-dependent growth arrest in prostate cancer

    Directory of Open Access Journals (Sweden)

    Gorin Frederic A

    2005-03-01

    Full Text Available Abstract Background Androgen withdrawal in normal prostate or androgen-dependent prostate cancer is associated with the downregulation of several glycolytic enzymes and with reduced glucose uptake. Although glycogen metabolism is known to regulate the intracellular glucose level its involvement in androgen response has not been studied. Methods We investigated the effects of androgen on glycogen phosphorylase (GP, glycogen synthase (GS and on glycogen accumulation in the androgen-receptor (AR reconstituted PC3 cell line containing either an empty vector (PC3-AR-V or vector with HPV-E7 (PC3-AR-E7 and the LNCaP cell line. Results Androgen addition in PC3 cells expressing the AR mimics androgen ablation in androgen-dependent prostate cells. Incubation of PC3-AR-V or PC3-AR-E7 cells with the androgen R1881 induced G1 cell cycle arrest within 24 hours and resulted in a gradual cell number reduction over 5 days thereafter, which was accompanied by a 2 to 5 fold increase in glycogen content. 24 hours after androgen-treatment the level of Glucose-6-P (G-6-P had increased threefold and after 48 hours the GS and GP activities increased twofold. Under this condition inhibition of glycogenolysis with the selective GP inhibitor CP-91149 enhanced the increase in glycogen content and further reduced the cell number. The androgen-dependent LNCaP cells that endogenously express AR responded to androgen withdrawal with growth arrest and increased glycogen content. CP-91149 further increased glycogen content and caused a reduction of cell number. Conclusion Increased glycogenesis is part of the androgen receptor-mediated cellular response and blockage of glycogenolysis by the GP inhibitor CP-91149 further increased glycogenesis. The combined use of a GP inhibitor with hormone therapy may increase the efficacy of hormone treatment by decreasing the survival of prostate cancer cells and thereby reducing the chance of cancer recurrence.

  8. Increased DHT levels in androgenic alopecia have been selected for to protect men from prostate cancer.

    Science.gov (United States)

    Bhargava, Shiva

    2014-04-01

    Androgenic alopecia, a condition characterized by increased levels of DHT could have been selected for due to the benefits that prostaglandin D2 (PGD(2)) has on the prostate. A DHT metabolite can increase the transcription of prostaglandin D2 synthase through estrogen receptor beta. The increase of PGD(2) can decrease the risk of prostate cancer and proliferation of prostate cancer cells. Therefore, the mechanisms behind male pattern baldness may also curtail the advancement of prostate cancer. PMID:24548754

  9. Combination of external irradiation and androgen suppression for prostate cancer: Facts and questions

    International Nuclear Information System (INIS)

    The combination of radiotherapy and androgen suppression with luteinizing hormone releasing hormone agonist is mainly devoted to locally advanced prostate cancer and intermediate or poor risk localized prostate cancer. They are based on phase III randomized trials which have shown that for locally advanced prostate cancer, a four-month complete androgen blockade initiated two months prior radiotherapy and stopped at the completion of radiotherapy increased overall survival in patients with Gleason scores 2-6, meanwhile, an adjuvant long-term androgen suppression (2.5 to three years) improved significantly the overall survival. Complete androgen blockade with a four to six months duration, combined with external irradiation, enhanced the overall survival in patients with intermediate or poor risk localized prostate cancer. (authors)

  10. Tubulin-Targeting Chemotherapy Impairs Androgen Receptor Activity in Prostate Cancer

    OpenAIRE

    Zhu, Meng-Lei; Horbinski, Craig; Garzotto, Mark; Qian, David Z.; Beer, Tomasz M.; Kyprianou, Natasha

    2010-01-01

    Recent insights into the regulation of the androgen receptor (AR) activity led to novel therapeutic targeting of AR function in prostate cancer patients. Docetaxel is an approved chemotherapy for treatment of castration-resistant-prostate cancer (CRPC), but the mechanism underlying the action of this tubulin-targeting drug is not fully understood. This study investigates the contribution of microtubules and the cytoskeleton to androgen-mediated signaling, and the consequences of their inhibit...

  11. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer

    OpenAIRE

    Fizazi, Karim; Albiges, Laurence; Loriot, Yohann; Massard, Christophe

    2015-01-01

    Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Seve...

  12. Anti-androgen resistance in prostate cancer cells chronically induced by interleukin-1β

    OpenAIRE

    Staverosky, Julia A.; Zhu, Xin-Hua; Ha, Susan; Logan, Susan K.

    2013-01-01

    Chronic inflammation has been linked to cancer initiation and progression in a variety of tissues, yet the impact of acute and chronic inflammatory signaling on androgen receptor function has not been widely studied. In this report, we examine the impact of the inflammation-linked cytokine, interleukin-1β on androgen receptor function in prostate cancer cells. We demonstrate that acute interleukin-1β treatment inhibits the transcription of the androgen receptor gene itself, resulting in the r...

  13. Androgenic alopecia is not useful as an indicator of men at high risk of prostate cancer.

    NARCIS (Netherlands)

    Cremers, R.G.H.M.; Aben, K.K.H.; Vermeulen, S.; Heijer, M. den; Oort, I.M. van; Kiemeney, L.A.L.M.

    2010-01-01

    BACKGROUND: Androgens are assumed to play a central role in the pathophysiology of both prostate cancer (PC) and androgenic alopecia (AA). A correlation between the two phenotypes may be relevant for identification of men at high risk of PC. We evaluated the association between AA at different ages

  14. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV: consequences of deficient interferon-dependent antiviral defense

    Directory of Open Access Journals (Sweden)

    Hubbard Gene B

    2011-01-01

    Full Text Available Abstract Background Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. Methods The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors Results We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The

  15. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

    International Nuclear Information System (INIS)

    Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells. The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied in vitro in culture and in vivo in a xenograft or allograft tumor model. In vitro, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. In vivo studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further

  16. Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

    OpenAIRE

    Lallous, Nada; Volik, Stanislav V.; Awrey, Shannon; LeBlanc, Eric; Tse, Ronnie; Murillo, Josef; Singh, Kriti; Azad, Arun A.; Wyatt, Alexander W.; LeBihan, Stephane; Chi, Kim N.; Gleave, Martin E.; Paul S. Rennie; Collins, Colin C; Cherkasov, Artem

    2016-01-01

    Background The androgen receptor (AR) is a pivotal drug target for the treatment of prostate cancer, including its lethal castration-resistant (CRPC) form. All current non-steroidal AR antagonists, such as hydroxyflutamide, bicalutamide, and enzalutamide, target the androgen binding site of the receptor, competing with endogenous androgenic steroids. Several AR mutations in this binding site have been associated with poor prognosis and resistance to conventional prostate cancer drugs. In orde...

  17. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential.

    Science.gov (United States)

    Zimmer, Brenna M; Howell, Michelle E; Wei, Qin; Ma, Linlin; Romsdahl, Trevor; Loughman, Eileen G; Markham, Jonathan E; Seravalli, Javier; Barycki, Joseph J; Simpson, Melanie A

    2016-08-01

    Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD(+)-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen-dependent versus castration-resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration-resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and prostate-specific antigen (PSA) expression, as well as the androgen receptor (AR)-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration-resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression. PMID:27307252

  18. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    International Nuclear Information System (INIS)

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser81 and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  19. Camptothecin disrupts androgen receptor signaling and suppresses prostate cancer cell growth

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shicheng, E-mail: liusc59@yahoo.co.jp [Research and Development Department, Nipro Patch Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057 (Japan); Yuan, Yiming [Department of Geriatrics, West China Hospital, Sichuan University, Chengdu 610041 (China); Okumura, Yutaka; Shinkai, Norihiro; Yamauchi, Hitoshi [Research and Development Department, Nipro Patch Co., Ltd., 8-1, Minamisakae-cho, Kasukabe, Saitama 344-0057 (Japan)

    2010-04-02

    The androgen receptor (AR) is the main therapeutic target for treatment of metastatic prostate cancers. The present study demonstrates that the topoisomerase I inhibitor camptothecin selectively inhibits androgen-responsive growth of prostate cancer cells. Camptothecin strikingly inhibited mutated and wild-type AR protein expression in LNCaP and PC-3/AR cells. This inhibition coincided with decreased androgen-mediated AR phosphorylation at Ser{sup 81} and reduced androgen-mediated AR transcriptional activity in a dose-dependent manner. Additionally, camptothecin disrupted the association between AR and heat shock protein 90 and impeded binding of the synthetic androgen [{sup 3}H]R1881 to AR in LNCaP cells. Camptothecin also blocked androgen-induced AR nuclear translocation, leading to downregulation of the AR target gene PSA. In addition to decreasing the intracellular and secreted prostate-specific antigen (PSA) levels, camptothecin markedly inhibited androgen-stimulated PSA promoter activity. Collectively, our data reveal that camptothecin not only serves as a traditional genotoxic agent but, by virtue of its ability to target and disrupt AR, may also be a novel candidate for the treatment of prostate cancer.

  20. Duration of short-course androgen suppression therapy and the risk of death as a result of prostate cancer.

    LENUS (Irish Health Repository)

    D'Amico, Anthony V

    2011-12-10

    We evaluated whether the duration of androgen suppression therapy (AST) had an impact on the risk of prostate cancer-specific mortality (PCSM) in men with unfavorable-risk prostate cancer (PC) within established Gleason score (GS) categories.

  1. Influence of androgen deprivation therapy on choline PET/CT in recurrent prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dost, Rutger J.; Breeuwsma, Anthonius J.; Jong, Igle J. de [University of Groningen, University Medical Center Groningen, Department of Urology, Groningen (Netherlands); Glaudemans, Andor W.J.M. [University of Groningen, University Medical Center Groningen, Nuclear Medicine and Molecular Imaging, Groningen (Netherlands)

    2013-07-15

    Recurrent prostate cancer is usually treated by combining radiotherapy and androgen deprivation therapy. To stage the cancer, choline positron emission tomography (PET)/CT can be performed. It is generally thought that androgen deprivation therapy does not influence choline PET/CT. In this article we focus on the molecular backgrounds of choline and androgens, and the results of preclinical and clinical studies performed using PET/CT. Using PubMed, we looked for the relevant articles about androgen deprivation therapy and choline PET/CT. During ADT, a tendency of decreased uptake of choline in prostate cancer was observed, in particular in hormone-naive patients. We conclude that in order to prevent false-negative choline PET/CT scans androgen deprivation should be withheld prior to scanning, especially in hormone-naive patients. (orig.)

  2. Influence of androgen deprivation therapy on choline PET/CT in recurrent prostate cancer

    International Nuclear Information System (INIS)

    Recurrent prostate cancer is usually treated by combining radiotherapy and androgen deprivation therapy. To stage the cancer, choline positron emission tomography (PET)/CT can be performed. It is generally thought that androgen deprivation therapy does not influence choline PET/CT. In this article we focus on the molecular backgrounds of choline and androgens, and the results of preclinical and clinical studies performed using PET/CT. Using PubMed, we looked for the relevant articles about androgen deprivation therapy and choline PET/CT. During ADT, a tendency of decreased uptake of choline in prostate cancer was observed, in particular in hormone-naive patients. We conclude that in order to prevent false-negative choline PET/CT scans androgen deprivation should be withheld prior to scanning, especially in hormone-naive patients. (orig.)

  3. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor - Synergistic action of quercetin and curcumin.

    Science.gov (United States)

    Sharma, Vikas; Kumar, Lokesh; Mohanty, Sujit K; Maikhuri, Jagdamba P; Rajender, Singh; Gupta, Gopal

    2016-08-15

    Epigenetic repression of Androgen Receptor (AR) gene by hypermethylation of its promoter causes resistance in prostate cancer (CaP) to androgen deprivation therapy with anti-androgens. Some dietary phytocompounds like quercetin (Q) and curcumin (C) with reported DNMT-inhibitory activity were tested for their ability to re-express the AR in AR-negative CaP cell lines PC3 and DU145. Combined treatment with Q+C was much more effective than either Q or C in inhibiting DNMT, causing global hypomethylation, restoring AR mRNA and protein levels and causing apoptosis via mitochondrial depolarization of PC3 and DU145. The functional AR protein expressed in Q+C treated cells sensitized them to dihydrotestosterone (DHT)-induced proliferation, bicalutamide-induced apoptosis, bound to androgen response element to increase luciferase activity in gene reporter assay and was susceptible to downregulation by AR siRNA. Bisulfite sequencing revealed high methylation of AR promoter CpG sites in AR-negative DU145 and PC3 cell lines that was significantly demethylated by Q+C treatment, which restored AR expression. Notable synergistic effects of Q+C combination in re-sensitizing androgen refractory CaP cells to AR-mediated apoptosis, their known safety in clinical use, and epidemiological evidences relating their dietary consumption with lower cancer incidences indicate their potential for use in chemoprevention of androgen resistance in prostate cancer. PMID:27132804

  4. Uncovering the Roles of miRNAs and Their Relationship with Androgen Receptor in Prostate Cancer

    OpenAIRE

    ChunJiao, Song; Huan, Chen; ChaoYang, Xu; GuoMei, Ru

    2014-01-01

    Prostate cancer (PCa) is the second most commonly occurring malignant tumor in Europe and America. Normal and neoplastic growth of prostate gland are dependent on androgen receptor (AR) expression and function. PCa is driven by androgen and its receptor, and they continue to be the key drivers of castration-resistant prostate cancer (CRPC). CRPC is the terminal stage of PCa and seriously jeopardizes the patient's quality of life and lifespan. miRNAs are small noncoding RNAs, 18–25 nt in lengt...

  5. Androgens and estrogens in benign prostatic hyperplasia: past, present and future.

    Science.gov (United States)

    Nicholson, Tristan M; Ricke, William A

    2011-01-01

    Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common clinical problems in urology. While the precise molecular etiology remains unclear, sex steroids have been implicated in the development and maintenance of BPH. Sufficient data exists linking androgens and androgen receptor pathways to BPH and use of androgen reducing compounds, such as 5α-reductase inhibitors which block the conversion of testosterone into dihydrotestosterone, are a component of the standard of care for men with LUTS attributed to an enlarged prostate. However, BPH is a multifactorial disease and not all men respond well to currently available treatments, suggesting factors other than androgens are involved. Testosterone, the primary circulating androgen in men, can also be metabolized via CYP19/aromatase into the potent estrogen, estradiol-17β. The prostate is an estrogen target tissue and estrogens directly and indirectly affect growth and differentiation of prostate. The precise role of endogenous and exogenous estrogens in directly affecting prostate growth and differentiation in the context of BPH is an understudied area. Estrogens and selective estrogen receptor modulators (SERMs) have been shown to promote or inhibit prostate proliferation signifying potential roles in BPH. Recent research has demonstrated that estrogen receptor signaling pathways may be important in the development and maintenance of BPH and LUTS; however, new models are needed to genetically dissect estrogen regulated molecular mechanisms involved in BPH. More work is needed to identify estrogens and associated signaling pathways in BPH in order to target BPH with dietary and therapeutic SERMs.

  6. Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

    Directory of Open Access Journals (Sweden)

    Elahe A Mostaghel

    Full Text Available Factors influencing differential responses of prostate tumors to androgen receptor (AR axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1 dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015. In LuCaP96 tumors (T:DHT 10:1, survival was not improved despite similar DHT reduction (0.02 ng/gm. LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both, reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors, and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively, persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and

  7. Regulation of Androgen Receptor and Prostate Cancer Growth by Cyclin-dependent Kinase 5*

    OpenAIRE

    Hsu, Fu-Ning; Chen, Mei-Chih; Chiang, Ming-Ching; Lin, Eugene; Lee, Yueh-Tsung; Huang, Pao-Hsuan; Lee, Guan-Shun; Lin, Ho

    2011-01-01

    Prostate cancer is the most frequently diagnosed male malignancy. The normal prostate development and prostate cancer progression are mediated by androgen receptor (AR). Recently, the roles of cyclin-dependent kinase 5 (Cdk5) and its activator, p35, in cancer biology are explored one after another. We have previously demonstrated that Cdk5 may regulate proliferation of thyroid cancer cells. In addition, we also identify that Cdk5 overactivation can be triggered by drug treatments and leads to...

  8. Use of androgen deprivation therapy in prostate cancer:indications and prevalence

    Institute of Scientific and Technical Information of China (English)

    Roisin M Connolly; Michael A Carducci; Emmanuel S Antonarakis

    2012-01-01

    Androgens play a prominent role in the development,maintenance and progression of prostate cancer.The introduction of androgen deprivation therapies into the treatment paradigm for prostate cancer patients has resulted in a wide variety of benefits ranging from a survival advantage for those with clinically localized or locally advanced disease,to improvements in symptom control for patients with advanced disease.Controversies remain,however,surrounding the optimal timing,duration and schedule of these hormonal approaches.Newer hormonal manipulations such as abiraterone acetate have also been investigated and will broaden treatment options for men with prostate cancer.This review highlights the various androgen-directed treatment options available to men with prostate cancer,their specific indications and the evidence supporting each approach,as well as patterns of use of hormonal therapies.

  9. Expression, Function of the Human Androgen-Responsive Gene AD11 in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Shane W. Oram

    2007-08-01

    Full Text Available We have previously identified an androgen-responsive gene in rat prostate that shares homology with the acireductone dioxygenase (ARD/ARD′ family of metalbinding enzymes involved in methionine salvage. We found that the gene, aci-reductone dioxygenase 1 (ADI1, was downregulated in prostate cancer cells, whereas enforced expression of rat Adi1 in these cells caused apoptosis. Here we report the characterization of human ADI1 in prostate cancer. Androgens induced ADI1 expression in human prostate cancer LNCaP cells, which was not blocked by cycloheximide, indicating that ADI1 is a primary androgen-responsive gene. In human benign prostatic hyperplasia specimens, epithelial cells expressed ADI1. Immunohistochemistry of prostate tumor tissue microarrays showed that benign regions expressed more ADI1 than tumors, suggesting a suppressive role for ADI1 in prostate cancer. Bacterial lysates containing recombinant ADI1 produced a five-fold increase in aci-reductone decay over controls, demonstrating that ADI1 has ARD activity. We generated point mutations at key residues in the metal-binding site of ADI1 to disrupt ARD function, we found that these mutations did not affect intracellular localization, apoptosis, or colony formation suppression in human prostate cancer cells. Collectively, these observations argue that AD11 may check prostate cancer progression through apoptosis, that this activity does not require metal binding.

  10. Baseline Serum Testosterone in Men Treated With Androgen Deprivation Therapy and Radiotherapy for Localized Prostate Cancer

    International Nuclear Information System (INIS)

    Introduction: It is believed that men diagnosed with prostate cancer and a low baseline serum testosterone (BST) may have more aggressive disease, and it is frequently recommended they forgo testosterone replacement therapy. We used two large Phase III trials involving androgen deprivation therapy and external beam radiation therapy to assess the significance of a BST. Methods and Materials: All patients with a BST and complete data (n = 2,478) were included in this analysis and divided into four categories: 'Very Low BST' (VLBST) ≤16.5th percentile of BST (≤248 ng/dL; n = 408); 'Low BST' (LBST) >16.5th percentile and ≤33rd percentile (>248 ng/dL but ≤314 ng/dL; n = 415); 'Average BST' (ABST) >33rd percentile and ≤67th percentile (314-437 ng/dL; n = 845); and 'High BST' (HBST) >67th percentile (>437 ng/dL; n = 810). Outcomes included overall survival, distant metastasis, biochemical failure, and cause-specific survival. All outcomes were adjusted for the following covariates: treatment arm, BST, age (<70 vs. ≥70), prostate-specific antigen (PSA; <10 vs. 10 ≤ PSA <20 vs. 20 ≤), Gleason score (2-6 vs. 7 vs. 8-10); T stage (T1-T2 vs. T3-T4), and Karnofsky Performance Status (60-90 vs. 100). Results: On multivariable analysis age, Gleason score, and PSA were independently associated with an increased risk of biochemical failure, distant metastasis and a reduced cause-specific and overall survival (p < 0.05), but BST was not. Conclusions: BST does not affect outcomes in men treated with external beam radiation therapy and androgen deprivation therapy for prostate cancer.

  11. Androgen Receptor Expression and Cellular Proliferation During Transition from Androgen-Dependent to Recurrent Growth after Castration in the CWR22 Prostate Cancer Xenograft

    OpenAIRE

    Kim, Desok; Gregory, Christopher W.; French, Frank S.; Smith, Gary J.; Mohler, James L.

    2002-01-01

    Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 ± 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 ± 0.08). Cellular proliferation measured using Ki-67 revealed

  12. Loss of exogenous androgen dependence by prostate tumor cells is associated with elevated glucuronidation potential

    Science.gov (United States)

    Zimmer, Brenna M.; Howell, Michelle E.; Wei, Qin; Ma, Linlin; Romsdahl, Trevor; Loughman, Eileen G.; Markham, Jonathan E.; Seravalli, Javier; Barycki, Joseph J.; Simpson, Melanie A.

    2016-01-01

    Prostate epithelial cells control the potency and availability of androgen hormones in part by inactivation and elimination. UDP-glucose dehydrogenase (UGDH) catalyzes the NAD+-dependent oxidation of UDP-glucose to UDP-glucuronate, an essential precursor for androgen inactivation by the prostate glucuronidation enzymes UGT2B15 and UGT2B17. UGDH expression is androgen stimulated, which increases the production of UDP-glucuronate, and fuels UGT-catalyzed glucuronidation. In this study, we compared the glucuronidation potential and its impact on androgen-mediated gene expression in an isogenic LNCaP model for androgen dependent versus castration resistant prostate cancer. Despite significantly lower androgen-glucuronide output, LNCaP 81 castration resistant tumor cells expressed higher levels of UGDH, UGT2B15, and UGT2B17. However, the magnitude of androgen-activated UGDH and PSA expression, as well as the AR-dependent repression of UGT2B15 and UGT2B17, was blunted several-fold in these cells. Consistent with these results, the ligand-activated binding of AR to the PSA promoter and subsequent transcriptional activation were also significantly reduced in castration resistant cells. Analysis of the UDP-sugar pools and flux through pathways downstream of UDP-glucuronate production revealed that these glucuronidation precursor metabolites were channeled through proteoglycan and glycosaminoglycan biosynthetic pathways, leading to increased surface expression of Notch 1. Knockdown of UGDH diminished Notch1 and increased glucuronide output. Overall, these results support a model in which the aberrant partitioning of UDP-glucuronate and other UDP-sugars into alternative pathways during androgen deprivation contributes to the loss of prostate tumor cell androgen sensitivity by promoting altered cell surface proteoglycan expression. PMID:27307252

  13. Antiandrogens act as selective androgen receptor modulators at the proteome level in prostate cancer cells.

    Science.gov (United States)

    Brooke, Greg N; Gamble, Simon C; Hough, Michael A; Begum, Shajna; Dart, D Alwyn; Odontiadis, Michael; Powell, Sue M; Fioretti, Flavia M; Bryan, Rosie A; Waxman, Jonathan; Wait, Robin; Bevan, Charlotte L

    2015-05-01

    Current therapies for prostate cancer include antiandrogens, inhibitory ligands of the androgen receptor, which repress androgen-stimulated growth. These include the selective androgen receptor modulators cyproterone acetate and hydroxyflutamide and the complete antagonist bicalutamide. Their activity is partly dictated by the presence of androgen receptor mutations, which are commonly detected in patients who relapse while receiving antiandrogens, i.e. in castrate-resistant prostate cancer. To characterize the early proteomic response to these antiandrogens we used the LNCaP prostate cancer cell line, which harbors the androgen receptor mutation most commonly detected in castrate-resistant tumors (T877A), analyzing alterations in the proteome, and comparing these to the effect of these therapeutics upon androgen receptor activity and cell proliferation. The majority are regulated post-transcriptionally, possibly via nongenomic androgen receptor signaling. Differences detected between the exposure groups demonstrate subtle changes in the biological response to each specific ligand, suggesting a spectrum of agonistic and antagonistic effects dependent on the ligand used. Analysis of the crystal structures of the AR in the presence of cyproterone acetate, hydroxyflutamide, and DHT identified important differences in the orientation of key residues located in the AF-2 and BF-3 protein interaction surfaces. This further implies that although there is commonality in the growth responses between androgens and those antiandrogens that stimulate growth in the presence of a mutation, there may also be influential differences in the growth pathways stimulated by the different ligands. This therefore has implications for prostate cancer treatment because tumors may respond differently dependent upon which mutation is present and which ligand is activating growth, also for the design of selective androgen receptor modulators, which aim to elicit differential proteomic

  14. Androgen-deprivation therapy versus radical prostatectomy as monotherapy among clinically localized prostate cancer patients

    Directory of Open Access Journals (Sweden)

    Liu J

    2013-06-01

    Full Text Available Jinan Liu,1 Lizheng Shi,2,3 Oliver Sartor,3 Richard Culbertson2,31HealthCore, Wilmington, DE, USA; 2School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA; 3School of Medicine, Tulane University, New Orleans, LA, USABackground: The most recent randomized controlled trial in a predominantly prostate-specific antigen-detected prostate cancer (PC population found a nonsignificant reduction in mortality from radical prostatectomy (RP compared to conservative management. The optimal treatment for clinically localized prostate cancer is anything but clear. The PC-specific mortality and all-cause mortality were compared between primary androgen-deprivation treatment (PADT and RP, both as monotherapy, among clinically localized PC patients.Methods: A retrospective cohort study among PC patients in Surveillance, Epidemiology and End Results-Medicare data with a median follow up of 2.87 years in the PADT cohort and 2.95 years in the RP cohort. Propensity score-matching was employed to adjust for the observed selection bias. PC-specific mortality and all-cause mortality were modeled using the Fine and Gray competing risk model and Cox proportional hazards model, respectively. The independent variables in these models included age, race, Gleason score risk groups, T-score, prostate-specific antigen, Charlson comorbidity, and index year of treatment initiation.Results: After propensity score-matching, there were 1624 in the PADT cohort and 1624 in the RP cohort. All baseline values were comparable (all P-values >0.35. There were a total of 266 deaths (16.38% and 60 (3.69% PC-specific deaths among PADT recipients, while there were 56 (3.45% deaths and four (0.25% PC-specific deaths among RP recipients. According to the Kaplan–Meier estimation, the 8-year survival rate was 43.39% in the PADT cohort and 79.62% in the RP cohort. PADT was associated with increased risk of overall mortality (hazard ratio = 2.98, 95% confidence

  15. Radiation therapy and androgen deprivation in the management of high risk prostate cancer

    International Nuclear Information System (INIS)

    The combined use of radiation therapy (RT) and androgen deprivation for patients with localized high-risk prostate cancer is commonly accepted as the standard treatment among uro-oncologists. Preclinical studies have provided rationale for the use of this combination. Additionally, results of phase 3 studies using conventional doses of RT have supported the combined approach. Other phase 3 studies have also shown a benefit for using higher doses of RT; however, the role of androgen deprivation in this context is not clear. The optimal duration of the androgen deprivation, in both the neoadjuvant and adjuvant setting, is still under investigation. This article critically reviews the data on the use of RT combined with androgen deprivation for the treatment of high-risk prostate cancer with emphasis on the results of phase 3 trials. (author)

  16. Radiation therapy and androgen deprivation in the management of high risk prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Dal Pra, Alan; Cury, Fabio L.; Souhami, Luis, E-mail: luis.souhami@muhc.mcgill.c [McGill University Health Centre, Montreal, QC (Canada). Dept. of Oncology. Division of Radiation Oncology

    2011-03-15

    The combined use of radiation therapy (RT) and androgen deprivation for patients with localized high-risk prostate cancer is commonly accepted as the standard treatment among uro-oncologists. Preclinical studies have provided rationale for the use of this combination. Additionally, results of phase 3 studies using conventional doses of RT have supported the combined approach. Other phase 3 studies have also shown a benefit for using higher doses of RT; however, the role of androgen deprivation in this context is not clear. The optimal duration of the androgen deprivation, in both the neoadjuvant and adjuvant setting, is still under investigation. This article critically reviews the data on the use of RT combined with androgen deprivation for the treatment of high-risk prostate cancer with emphasis on the results of phase 3 trials. (author)

  17. New Insights into the Androgen-Targeted Therapies and Epigenetic Therapies in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Abhijit M. Godbole

    2011-01-01

    Full Text Available Prostate cancer is the most common cancer in men in the United States, and it is the second leading cause of cancer-related death in American men. The androgen receptor (AR, a receptor of nuclear family and a transcription factor, is the most important target in this disease. While most efforts in the clinic are currently directed at lowering levels of androgens that activate AR, resistance to androgen deprivation eventually develops. Most prostate cancer deaths are attributable to this castration-resistant form of prostate cancer (CRPC. Recent work has shed light on the importance of epigenetic events including facilitation of AR signaling by histone-modifying enzymes, posttranslational modifications of AR such as sumoylation. Herein, we provide an overview of the structure of human AR and its key structural domains that can be used as targets to develop novel antiandrogens. We also summarize recent findings about the antiandrogens and the epigenetic factors that modulate the action of AR.

  18. Anemia in patients on combined androgen block therapy for prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Li-XinQian; Li-XinHua; Hong-FeiWu; Yuan-GengSui; Shuang-GuanCheng; WeiZhang,JieLi; Xin-RuWang

    2004-01-01

    Aim: To study the effect of combined androgen block therapy on hemoglobin and hematocrit values in patients with prostate cancer. Methods: One hundred and thirty-six patients with adenocarcinoma of prostate were treated with combined androgen block (orchiectomy and flutamide 250 mg, tid). Complete blood counts were determined before and after 1,2,3,6,9 and 12 months of therapy. Results: The hemoglobin and hematocrit levels declined significantly in all patients and at all the time points after treatment (P<0.05). Conclusion: Prostate cancer patients treated with combined androgen block would develop obvious anemia. Recombinant human erythropoietin can be used to treat patients with severe anemia. (Asian J Androl 2004 Dec;6: 383-384)

  19. SOCS2 mediates the cross talk between androgen and growth hormone signaling in prostate cancer

    DEFF Research Database (Denmark)

    Iglesias Gato, Diego; Chuan, Yin Choy; Wikström, Pernilla;

    2014-01-01

    ) as mediator of the cross talk between androgens and GH signals in the prostate and its potential role as tumor suppressor in prostate cancer (PCa). We observed that SOCS2 protein levels assayed by immunohistochemistry are elevated in hormone therapy-naive localized prostatic adenocarcinoma in comparison...... with benign tissue. In contrast, however, castration-resistant bone metastases exhibit reduced levels of SOCS2 in comparison with localized or hormone naive, untreated metastatic tumors. In PCa cells, SOCS2 expression is induced by androgens through a mechanism that requires signal transducer and activator...... to GH. Our results suggest that the use of GH-signaling inhibitors could be of value as a complementary treatment for castration-resistant PCa.Summary: Androgen induced SOCS2 ubiquitin ligase expression and inhibited GH signaling as well as cell proliferation and invasion in PCa, whereas reduced SOCS2...

  20. Prostate Cancer Survivorship: Prevention and Treatment of the Adverse Effects of Androgen Deprivation Therapy

    OpenAIRE

    Saylor, Philip J.; Keating, Nancy Lynn; Smith, Matthew Raymond

    2009-01-01

    ABSTRACT BACKGROUND More than one-third of the estimated 2 million prostate cancer survivors in the United States receive androgen deprivation therapy (ADT). This population of mostly older men is medically vulnerable to a variety of treatment-associated adverse effects. MEASUREMENTS AND RESULTS Androgen-deprivation therapy (ADT) causes loss of libido, vasomotor flushing, anemia, and fatigue. More recently, ADT has been shown to accelerate bone loss, increase fat mass, increase cholesterol an...

  1. Targeting Alternative Sites on the Androgen Receptor to Treat Castration-Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Paul S. Rennie

    2013-06-01

    Full Text Available Recurrent, metastatic prostate cancer continues to be a leading cause of cancer-death in men. The androgen receptor (AR is a modular, ligand-inducible transcription factor that regulates the expression of genes that can drive the progression of this disease, and as a consequence, this receptor is a key therapeutic target for controlling prostate cancer. The current drugs designed to directly inhibit the AR are called anti-androgens, and all act by competing with androgens for binding to the androgen/ligand binding site. Unfortunately, with the inevitable progression of the cancer to castration resistance, many of these drugs become ineffective. However, there are numerous other regulatory sites on this protein that have not been exploited therapeutically. The regulation of AR activity involves a cascade of complex interactions with numerous chaperones, co-factors and co-regulatory proteins, leading ultimately to direct binding of AR dimers to specific DNA androgen response elements within the promoter and enhancers of androgen-regulated genes. As part of the family of nuclear receptors, the AR is organized into modular structural and functional domains with specialized roles in facilitating their inter-molecular interactions. These regions of the AR present attractive, yet largely unexploited, drug target sites for reducing or eliminating androgen signaling in prostate cancers. The design of small molecule inhibitors targeting these specific AR domains is only now being realized and is the culmination of decades of work, including crystallographic and biochemistry approaches to map the shape and accessibility of the AR surfaces and cavities. Here, we review the structure of the AR protein and describe recent advancements in inhibiting its activity with small molecules specifically designed to target areas distinct from the receptor’s androgen binding site. It is anticipated that these new classes of anti-AR drugs will provide an additional

  2. A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors.

    Science.gov (United States)

    Kumar, Rajeev; Verma, Vikas; Sharma, Vikas; Jain, Ashish; Singh, Vishal; Sarswat, Amit; Maikhuri, Jagdamba P; Sharma, Vishnu L; Gupta, Gopal

    2015-03-15

    Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P<0.01) and increased expression of ER-β target TNF-α (P<0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization.

  3. 基因沉默白介素8对激素非依赖前列腺癌干细胞的生物特性的影响%Effect of Interleukin-8 Silencing on Androgen-independent Prostate Cancer Stem Cells

    Institute of Scientific and Technical Information of China (English)

    孙梦奎; 张纪恒; 崔韵; 金杰

    2016-01-01

    Objective To explore the effect of IL-8 silencing via small interfering RNA on androgen-independent pros-tate cancer stem cells and drug sensitive.Methods DU145 cells transfected with different concentration of IL-8 siRNA were col-lected .The percentage of ALDH+cells were detected by flow cytometry.The sphere formation rate and cloning efficiency were de-termined by sphere formation assay and clonogenic assay.The viability of cells was detected by CCK-8 assay.The phosphorylation of Akt was evaluated by Western blot.Results The percentage of ALDH+cells were declined under different concentration of IL-8 siRNA in DU145 cells.Sphere formation rate and cloning efficiency of prostate cancer stem cells were decreased by siRNA. The viability of IL-8 silencing DU145 cells was significantly suppressed compared with control groups and the Akt phosphorylation was activated.Conclusion IL-8 siRNA can eliminate androgen-independent prostate cancer stem cells and suppresses the self-renew and clonogenic capacity of prostate cancer stem cells.IL-8 silencing sensitizes prostate cancer stem cells to docetaxel and inactivates the Akt pathway.%目的:探讨小干扰RNA沉默激素非依赖前列腺癌DU145细胞白介素8基因对肿瘤干细胞生物学特性及耐药性的影响。方法用不同剂量的小干扰RNA沉默激素非依赖前列腺癌DU145细胞IL-8基因,应用流式仪检测AL-DH阳性细胞比例的变化。采用悬浮细胞成球和克隆形成实验分别观察肿瘤干细胞自我更新和体外成瘤能力的变化。Annexin V-PE/7-AAD细胞凋亡双染试剂盒检测细胞凋亡率的变化,Western-blot法分析Akt蛋白的变化。结果 DU145细胞IL-8基因的沉默能降低肿瘤干细胞的比例,显著降低肿瘤干细胞悬浮细胞成球率和克隆形成率。多西他赛能显著抑制IL-8基因沉默DU145细胞的活性。 Western-blot显示Akt的磷酸化被显著抑制。结论 IL-8基因的沉默能显著抑制激素非依赖前列

  4. A novel finding: Anti-androgen flutamide kills androgen-independent PC-3 cells: A radiolabelled methyl-choline incorporation into tumour cells

    International Nuclear Information System (INIS)

    Full text: [Methyl-11C]-choline was introduced to image many types of cancers especially the prostate cancer. Al-Saeedi et al. reported that the incorporation of [Methyl-3H]-choline into breast tumour (MCF-7) cells correlated strongly with proliferation as determined by [Methyl-14C]- thymidine uptake. Also, Al-Saeedi, et al. showed that the chemotherapy using MCF-7 cells treated with 5-Fluorouracil (5-FU) induced modulation in [Methyl-3H]-choline incorporation and certain mechanisms for this modulation were reported. In this study, the androgen-dependent prostate tumour (LNCaP) cells were treated with the well known pure anti-androgen drug, flutamide, for three days. The cells were then incubated with [Methyl-3H]-choline for 10 mint to detect the effect of flutamide on both cell proliferation and choline incorporation. At the same time, a preliminary work was established using androgen-independent PC-3 cells treated with flutamide as controls in this study. PC-3 cells were treated with a range of doses of flutamide inhibiting growth by 20[Methyl-3H]-Choline Incorporation into MCF-7 Cells: Correlation with Proliferation: choline kinase and phospholipase D assay. [Methyl-3H]-Choline Incorporation into MCF-7 Cells: Correlation with Proliferation: choline kinase and phospholipase D assay. - 70%. Treated and control cells were incubated with [Methyl-3H]-choline for 10 min, then in non-radioactive medium to simulate the rapid blood clearance of [Methyl-11C]-choline tracer in control and treated PC-3 cells, and then extracted with organic and aqueous solvents to determine its effect on the intracellular distribution of this tracer. Interesting results showed that flutamide killed the androgen-independent prostate cancer cells, PC-3 and mechanisms responsible for flutamide-induced modulation on [Methyl-3H]- choline incorporation were reported. The PC-3 cells' proliferation was inhibited by flutamide. In addition, treatment of PC-3 cells with flutamide for 3 days resulted

  5. LncRNA HOTAIR Enhances the Androgen-Receptor-Mediated Transcriptional Program and Drives Castration-Resistant Prostate Cancer

    OpenAIRE

    Ali Zhang; Jonathan C. Zhao; Jung Kim; Ka-wing Fong; Yeqing Angela Yang; Debabrata Chakravarti; Yin-Yuan Mo; Jindan Yu

    2015-01-01

    SUMMARY Understanding the mechanisms of androgen receptor (AR) activation in the milieu of low androgen is critical to effective treatment of castration-resistant prostate cancer (CRPC). Here, we report HOTAIR as an androgen-repressed lncRNA, and, as such, it is markedly upregulated following androgen deprivation therapies and in CRPC. We further demonstrate a distinct mode of lncRNA-mediated gene regulation, wherein HOTAIR binds to the AR protein to block its interaction with the E3 ubiquiti...

  6. Is there a relationship between androgenic alopecia and benign prostatic hyperplasia?

    Science.gov (United States)

    Dastgheib, Ladan; Shirazi, Mehdi; Moezzi, Iman; Dehghan, Saber; Sadati, Maryam-Sadat

    2015-01-01

    Androgenic alopecia as a physiologic process and benign prostatic hyperplasia (BPH) as a pathologic process in the older population are androgen-dependent processes influenced by 5-alpha reductase enzyme which converts testosterone to dihydrotestosterone. This cross sectional study was done to evaluate the relationship between androgenic alopecia and BPH. 150 men older than 50 years old, who presented to the free prostate screening clinic, were included. They were asked about urinary symptoms. PSA level, prostate volume with sonography and alopecia grading using Hamilton-Norwood classification (grade I to VII) were evaluated. Analysis was done by SPSS statistical method. 59.6% of men had mild alopecia (grade I, II, III), 34.1% had moderate alopecia (grade IV, V) and 6.3% had severe alopecia (grade VI, VII).The mean PSA level was 1.37 ± 1.48 ng/ml. The minimum PSA level was 0.1 ng/ml, and the maximum level was 6.8 ng/ml. The mean prostate volume was 37.85 ± 21.85cc. The minimum prostate size was 10 ml, and the maximum volume was 173 ml. The mean international prostate symptom score (IPSS) was 7.6 ± 6.11 with the minimum score 0 and the maximum score 27. However, no relationship between these parameters and androgenic alopecia was detected. This study showed that there is no relationship between androgenic alopecia, PSA level, IPSS, and prostate volume. Occurrence of alopecia in younger age and a positive family history correlated with a higher grade of alopecia. PMID:25597602

  7. Is there a relationship between androgenic alopecia and benign prostatic hyperplasia?

    Directory of Open Access Journals (Sweden)

    Ladan Dastgheib

    2015-01-01

    Full Text Available Androgenic alopecia as a physiologic process and benign prostatic hyperplasia (BPH as a pathologic process in the older population are androgen-dependent processes influenced by 5-alpha reductase enzyme which converts testosterone to dihydrotestosterone. This cross sectional study was done to evaluate the relationship between androgenic alopecia and BPH. 150 men older than 50 years old, who presented to the free prostate screening clinic, were included. They were asked about urinary symptoms. PSA level, prostate volume with sonography and alopecia grading using Hamilton-Norwood classification (grade I to VII were evaluated. Analysis was done by SPSS statistical method. 59.6% of men had mild alopecia (grade I, II, III, 34.1% had moderate alopecia (grade IV, V and 6.3% had severe alopecia (grade VI, VII.The mean PSA level was 1.37 ± 1.48 ng/ml. The minimum PSA level was 0.1 ng/ml, and the maximum level was 6.8 ng/ml. The mean prostate volume was 37.85 ± 21.85cc. The minimum prostate size was 10 ml, and the maximum volume was 173 ml. The mean international prostate symptom score (IPSS was 7.6 ± 6.11 with the minimum score 0 and the maximum score 27. However, no relationship between these parameters and androgenic alopecia was detected. This study showed that there is no relationship between androgenic alopecia, PSA level, IPSS, and prostate volume. Occurrence of alopecia in younger age and a positive family history correlated with a higher grade of alopecia.

  8. Morphology of the epithelial cells and expression of androgen receptor in rat prostate dorsal lobe in experimental hyperprolactinemia.

    OpenAIRE

    Marcin Wylot; Wojciech Głabowski; Maria Laszczyńska; Sylwia Słuczanowska-Głabowska

    2006-01-01

    The effect of hyperprolactinemia on the prostate has not been well investigated. Since androgens play an important role in prostate development, growth and function, the goal of the present study was to estimate the influence of hyperprolactinemia on expression of the androgen receptor (AR) in rat epithelial cells of prostate dorsal lobe and on morphology of these cells. Studies were performed on sexually mature male Wistar rats. The experimental group rats received metoclopramide (MCP) intra...

  9. A method for tissue extraction and determination of prostate concentrations of endogenous androgens by radioimmunoassay

    International Nuclear Information System (INIS)

    A method for simultaneously determining concentrations of major androgens in prostate has been developed. Extraction techniques used to isolate the androgens from minced tissue include homogenization with high-speed blades in Delsal's solvent mixture, adsorption to silica gel, followed by column and one thin-layer chromatography (TLC). Radioimmunoassays (RIA) of small aliquots of TLC eluates are used to quantitate picogram amounts of 5α-dihydrotestosterone (DHT) and 5α-androstanediols (Diol) and to estimate testosterone (T) and androstenedione (Ad). Contamination of blanks was reduced to RIA sensitivity limits primarily by treatment of glassware in a self-cleaning oven. The specificity of the method for each androgen was established by TLC separations of known prostate metabolites, antisera specificities, and parallelism of sample aliquots to androgen RIA standards. The overall precision, in terms of coefficients of variation, was 21% for DHT and 24% for Diol. T and Ad could not be measured with acceptable precision because their very low concentrations in prostate (<=0.5 ng/g tissue) were less than RIA sensitivity limits. Accuracy studies indicated recoveries ranging from 96% for Diol to 121% for DHT. In human benign hypertrophic prostate tissue, DHT averaged 153 ng/g soluble protein (5.8 ng/g tissue) which was 17 times higher than values obtained in human spleen and kidney; Diol in prostate showed no consistent differences from values noted in kidney or spleen

  10. Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells

    OpenAIRE

    Chen, Mengqian; Tanner, Matthew; Levine, Alice C.; Levina, Elina; Ohouo, Patrice; Buttyan, Ralph

    2009-01-01

    Hedgehog signaling is thought to play a role in several human cancers including prostate cancer. Although prostate cancer cells express many of the gene products involved in hedgehog signaling, these cells are refractory to the canonical signaling effects of exogenous hedgehog ligands or to activated Smoothened, the hedgehog-regulated mediator of Gli transcriptional activation. Here, we show that the expression of hedgehog ligands and some hedgehog target genes are regulated by androgen in th...

  11. A comprehensive bone-health management approach for men with prostate cancer receiving androgen deprivation therapy

    OpenAIRE

    Lee, C. E.; Leslie, W.D.; Czaykowski, P.; Gingerich, J.; Geirnaert, M.; Lau, Y.K.J.

    2011-01-01

    For advanced and metastatic prostate cancer, androgen deprivation therapy (adt) is the mainstay of treatment. Awareness of the potential bone-health complications consequent to adt use is increasing. Many studies have shown that prolonged adt leads to significant bone loss and increased fracture risk that negatively affect quality of life. Clinical practice guidelines for preserving bone health in men with prostate cancer on adt vary across Canada. This paper reviews recent studies on bone he...

  12. Detection of androgen receptor in human prostatic adenoma by the autoradiography

    International Nuclear Information System (INIS)

    We developed a new amplified method to detect the localization of androgen receptors within the human prostatic tissue specimens. The tissue sections were treated with 50 μl of 100 nM tritiated dihydrotestosterone (3H-DHT). The binding of 3H-DHT to receptors were demonstrated as silver grains on the stained tissue sections. The binding of 3H-DHT to the prostatic tissue was inhibited by additional non-radioactive DHT remarkably and by testosterone partially, but not affected by additional progesterone and 17#betta#-estradiol. No binding of 3H-DHT to the bladder tissue was found. These results showed that the binding of 3H-DHT to the prostatic tissue was a specific reaction of 3H-DHT and androgen receptor. Androgen receptors were seen in the nuclei and the cytoplasmas of glandular epithelial cells of prostate. However, stromal cells contained less abundant androgen receptors. The method reported here has several advantages in detecting the androgen receptor of the prostatic tissue in comparison with the radioreceptor assay and other histochemical methods. 1) The needle biopsied specimens are big enough to examine. 2) Morphological observation are also possible on the same specimen because the specimens are stained with hematoxylin simultaneously. Therefore, we can know the relative ratio of androgen receptor positive cells and negative cells. 3) Binding of 3H-DHT to the receptor with this method may be more specific than other histochemical methods, since binding of 3H-DHT to the receptor was inhibited by 200-fold excess of non-radioactive DHT. 4) Treatment of scintillator, fluorographic technique shortens the exposure periods. The exposure periods are approximately six to twelve times shorter than that of the conventional autoradiography. (J.P.N.)

  13. Metabolic syndrome and androgen deprivation therapy in metabolic complications of prostate cancer patients

    Institute of Scientific and Technical Information of China (English)

    YUAN Jia-qi; XU Tao; ZHANG Xiao-wei; YU Lu-ping; LI Qing; LIU Shi-jun; HUANG Xiao-bo; WANG Xiao-feng

    2012-01-01

    Background Incidence of prostate cancer in Chinese males grows significantly in the past decades.Androgen deprivation therapy has been generally employed in the treatment of locally advanced and metastatic prostate cancer for many years,yet only little data was known about the metabolic syndrome in patients receiving hormonal therapy.This study described the prevalence and the changing trends of hormone-related metabolic complications,and analyzed their correlation with different therapies.Methods In 125 patients treated with castration or maximal androgen blockage for at least 12 months,metabolic indicators were analyzed.Results Totally,13.5% patients in castration group and 30.1% patients in maximal androgen blockage group were diagnosed metabolic syndrome 12 months after the beginning of treatments (x2=4.739,P=0.029).In castration group,increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 12,increased fasting plasma glucose and blood pressure were significant at the month 4.In maximal androgen blockage group,increased triglyceride and decreased high-density lipoprotein-cholesterol were significant at the month 4,increased fasting plasma glucose and blood pressure were significant at the month 8.Total testosterone and free testosterone in maximal androgen blockage group were significantly lower than castration group at all visits,which were proved to show positive or negative correlations with metabolic indications.Severity of metabolic complications in maximal androgen blockage group was generally more serious than people received castration,with significantly statistical difference or not.Trends of high-density lipoprotein-cholesterol and fasting plasma glucose were significant different between two kinds of therapy (P=0.005,P=0.019,respectively).Conclusions Prostate cancer patients receiving androgen deprivation therapy were at high risk of suffering metabolic syndrome.Severity of metabolic complications

  14. Androgen-targeted therapy induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: an opportunity for intervention

    Directory of Open Access Journals (Sweden)

    Mannan eNouri

    2014-12-01

    Full Text Available Androgens regulate biological pathways to promote proliferation, differentiation and survival of benign and malignant prostate tissue. Androgen receptor targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or androgen receptor function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation has been shown to activate both epithelial-to-mesenchymal transition (EMT and neuroendocrine transdifferentiation programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy in multiple human cancer types. Neuroendocrine transdifferentiation in prostate cancer is associated with resistance to therapy, visceral metastasis and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK and aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.

  15. A study of the prostate, androgens and sexual activity of male rats

    Directory of Open Access Journals (Sweden)

    Garcia Luis I

    2007-03-01

    Full Text Available Abstract Background The prostate is a sexual gland that produces important substances for the potency of sperm to fertilize eggs within the female reproductive tract, and is under complex endocrine control. Taking advantage of the peculiar behavioral pattern of copulating male rats, we developed experimental paradigms to determine the influence of sexual behavior on the level of serum testosterone, prostate androgen receptors, and mRNA for androgen receptors in male rats displaying up to four consecutive ejaculations. Methods The effect of four consecutive ejaculations was investigated by determining levels of (i testosterone in serum by solid phase RIA, (ii androgen receptors at the ventral prostate with Western Blots, and (iii androgen receptors-mRNA with RT-PCR. Data were analyzed with a one-way ANOVA followed by a post hoc application of Dunnett's test if required. Results The constant execution of sexual behavior did not produce any change in the weight of the ventral prostate. Serum testosterone increased after the second ejaculation, and remained elevated even after four ejaculations. The androgen receptor at the ventral prostate was higher after the first to third ejaculations, but returned suddenly to baseline levels after the fourth ejaculation. The level of mRNA increased after the first ejaculation, continued to increase after the second, and reached the highest peak after the third ejaculation; however, it returned suddenly to baseline levels after the fourth ejaculation. Conclusion Four consecutive ejaculations by sexually experienced male rats had important effects on the physiological responses of the ventral prostate. Fast responses were induced as a result of sexual behavior that involved an increase and decrease in androgen receptors after one and four ejaculations, respectively. However, a progressive response was observed in the elevation of mRNA for androgen receptors, which also showed a fast decrease after four

  16. New Prostate Cancer Treatment Target

    Science.gov (United States)

    Researchers have identified a potential alternative approach to blocking a key molecular driver of an advanced form of prostate cancer, called androgen-independent or castration-resistant prostate cancer.

  17. Dominant-negative androgen receptor inhibition of intracrine androgen-dependent growth of castration-recurrent prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mark A Titus

    Full Text Available BACKGROUND: Prostate cancer (CaP is the second leading cause of cancer death in American men. Androgen deprivation therapy is initially effective in CaP treatment, but CaP recurs despite castrate levels of circulating androgen. Continued expression of the androgen receptor (AR and its ligands has been linked to castration-recurrent CaP growth. PRINCIPAL FINDING: In this report, the ligand-dependent dominant-negative ARΔ142-337 (ARΔTR was expressed in castration-recurrent CWR-R1 cell and tumor models to elucidate the role of AR signaling. Expression of ARΔTR decreased CWR-R1 tumor growth in the presence and absence of exogenous testosterone (T and improved survival in the presence of exogenous T. There was evidence for negative selection of ARΔTR transgene in T-treated mice. Mass spectrometry revealed castration-recurrent CaP dihydrotestosterone (DHT levels sufficient to activate AR and ARΔTR. In the absence of exogenous testosterone, CWR-R1-ARΔTR and control cells exhibited altered androgen profiles that implicated epithelial CaP cells as a source of intratumoral AR ligands. CONCLUSION: The study provides in vivo evidence that activation of AR signaling by intratumoral AR ligands is required for castration-recurrent CaP growth and that epithelial CaP cells produce sufficient active androgens for CaP recurrence during androgen deprivation therapy. Targeting intracrine T and DHT synthesis should provide a mechanism to inhibit AR and growth of castration-recurrent CaP.

  18. A novel nuclear role for the Vav3 nucleotide exchange factor in androgen receptor coactivation in prostate cancer.

    Science.gov (United States)

    Rao, S; Lyons, L S; Fahrenholtz, C D; Wu, F; Farooq, A; Balkan, W; Burnstein, K L

    2012-02-01

    Increased androgen receptor (AR) transcriptional activity mediated by coactivator proteins may drive castration-resistant prostate cancer (CRPC) growth. Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), is overexpressed in human prostate cancers, particularly in models of CRPC progression. Vav3 coactivates AR in a Vav3 pleckstrin homology (PH) domain-dependent but GEF-independent manner. Ectopic expression of Vav3 in androgen-dependent human prostate cancer cells conferred robust castration-resistant xenograft tumor growth. Vav3 but not a Vav3 PH mutant greatly stimulated interaction between the AR amino and carboxyl termini (N-C interaction), which is required for maximal receptor transcriptional activity. Vav3 was distributed between the cytoplasm and nucleus with nuclear localization-dependent on the Vav3 PH domain. Membrane targeting of Vav3 abolished Vav3 potentiation of AR activity, whereas nuclear targeting of a Vav3 PH mutant rescued AR coactivation, suggesting that nuclear localization is an important function of the Vav3 PH domain. A nuclear role for Vav3 was further demonstrated by sequential chromatin immunoprecipitation assays, which revealed that Vav3 and AR were recruited to the same transcriptional complexes of an AR target gene enhancer. These data demonstrate the importance of Vav3 in CRPC and define a novel nuclear function of Vav3 in regulating AR activity.

  19. Preferred treatment frequency in patients receiving androgen deprivation therapy for advanced prostate cancer

    DEFF Research Database (Denmark)

    Fode, Mikkel; Nielsen, Torben K; Al-Hamadani, Muhammad;

    2014-01-01

    OBJECTIVE: The aim of this study was to assess patient preference regarding the length of treatment intervals of androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonists for prostate cancer. MATERIAL AND METHODS: The study was conducted as a questionnaire-based, cross...

  20. Grappling with the androgen receptor—a new approach for treating advanced prostate cancer

    OpenAIRE

    Thompson, Timothy C.

    2010-01-01

    In this issue of Cancer Cell, Andersen et al report on a small molecule that interacts with and blocks transactivation of the androgen receptor amino-terminal domain. This agent can overcome the shortcomings of clinically used antiandrogens, an important advance in the development of effective therapy for advanced prostate cancer.

  1. Steroidogenic enzymes and stem cell markers are upregulated during androgen deprivation in prostate cancer

    NARCIS (Netherlands)

    Pfeiffer, M.J.; Smit, F.P.; Sedelaar, J.P.M.; Schalken, J.A.

    2011-01-01

    Considerable levels of testosterone and dihydrotestosterone (DHT) are found in prostate cancer (PCa) tissue after androgen deprivation therapy. Treatment of surviving cancer-initiating cells and the ability to metabolize steroids from precursors may be the keystones for the appearance of recurrent t

  2. REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer

    DEFF Research Database (Denmark)

    Svensson, Charlotte; Ceder, Jens; Iglesias Gato, Diego;

    2014-01-01

    The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds...

  3. A partner monoclonal antibody to Moab 730 kills 100% of DU145 and PC3 androgen-independent cancer cells

    Indian Academy of Sciences (India)

    Hemant Kumar Vyas; Rahul Pal; Nirmal K Lohiya; G P Talwar

    2009-12-01

    A number of therapeutic options are available for patients with prostate carcinoma till the time that the tumour is hormone dependent. However, no fully effective therapy is available for the treatment of androgen-independent prostate carcinomas. Antibodies directed at epitopes unique to or overexpressed on the cancer cells could be of therapeutic utility. A monoclonal antibody (Moab) 2C4 has been generated, which binds with cells of two androgenindependent prostate cancers, DU145 and PC3, and does not bind to peripheral blood leukocytes (PBLs) of healthy donors. This antibody, along with the previously developed Moab 730, kills 100% of both DU145 and PC3 cells in the presence of complement and does not have a deleterious effect on PBLs of healthy males. The anti-tumour action of the two antibodies prevents the establishment of DU145 cell tumour in nude mice in vivo. Moab 2C4 in combination with 730 has potential for use as therapy for androgen-independent cancers.

  4. Androgen receptor non-nuclear regulation of prostate cancer cell invasion mediated by Src and matriptase.

    Science.gov (United States)

    Zarif, Jelani C; Lamb, Laura E; Schulz, Veronique V; Nollet, Eric A; Miranti, Cindy K

    2015-03-30

    Castration-resistant prostate cancers still depend on nuclear androgen receptor (AR) function despite their lack of dependence on exogenous androgen. Second generation anti-androgen therapies are more efficient at blocking nuclear AR; however resistant tumors still develop. Recent studies indicate Src is highly active in these resistant tumors. By manipulating AR activity in several different prostate cancer cell lines through RNAi, drug treatment, and the use of a nuclear-deficient AR mutant, we demonstrate that androgen acting on cytoplasmic AR rapidly stimulates Src tyrosine kinase via a non-genomic mechanism. Cytoplasmic AR, acting through Src enhances laminin integrin-dependent invasion. Active Matriptase, which cleaves laminin, is elevated within minutes after androgen stimulation, and is subsequently shed into the medium. Matriptase activation and shedding induced by cytoplasmic AR is dependent on Src. Concomitantly, CDCP1/gp140, a Matriptase and Src substrate that controls integrin-based migration, is activated. However, only inhibition of Matriptase, but not CDCP1, suppresses the AR/Src-dependent increase in invasion. Matriptase, present in conditioned medium from AR-stimulated cells, is sufficient to enhance invasion in the absence of androgen. Thus, invasion is stimulated by a rapid but sustained increase in Src activity, mediated non-genomically by cytoplasmic AR, leading to rapid activation and shedding of the laminin protease Matriptase.

  5. MicroRNAs are mediators of androgen action in prostate and muscle.

    Directory of Open Access Journals (Sweden)

    Ramesh Narayanan

    Full Text Available Androgen receptor (AR function is critical for the development of male reproductive organs, muscle, bone and other tissues. Functionally impaired AR results in androgen insensitivity syndrome (AIS. The interaction between AR and microRNA (miR signaling pathways was examined to understand the role of miRs in AR function. Reduction of androgen levels in Sprague-Dawley rats by castration inhibited the expression of a large set of miRs in prostate and muscle, which was reversed by treatment of castrated rats with 3 mg/day dihydrotestosterone (DHT or selective androgen receptor modulators. Knockout of the miR processing enzyme, DICER, in LNCaP prostate cancer cells or tissue specifically in mice inhibited AR function leading to AIS. Since the only function of miRs is to bind to 3' UTR and inhibit translation of target genes, androgens might induce miRs to inhibit repressors of AR function. In concordance, knock-down of DICER in LNCaP cells and in tissues in mice induced the expression of corepressors, NCoR and SMRT. These studies demonstrate a feedback loop between miRs, corepressors and AR and the imperative role of miRs in AR function in non-cancerous androgen-responsive tissues.

  6. Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, Jacob; Schmidt, Jakob Friis; Christensen, Jesper Frank;

    2013-01-01

    (FC) Prostate' study is a randomized trial comparing the effects of soccer training with standard treatment approaches on body composition, cardiovascular function, physical function parameters, glucose tolerance, bone health, and patient-reported outcomes in men undergoing ADT for prostate cancer.......Androgen deprivation therapy (ADT) is a cornerstone in the treatment of advanced prostate cancer. Adverse musculoskeletal and cardiovascular effects of ADT are widely reported and investigations into the potential of exercise to ameliorate the effects of treatment are warranted. The 'Football Club...

  7. Concurrent Androgen Deprivation Therapy During Salvage Prostate Radiotherapy Improves Treatment Outcomes in High-Risk Patients

    International Nuclear Information System (INIS)

    Purpose: To determine whether concurrent androgen deprivation therapy (ADT) during salvage radiotherapy (RT) improves prostate cancer treatment outcomes. Methods and Materials: A total of 630 postprostatectomy patients were retrospectively identified who were treated with three-dimensional conformal RT. Of these, 441 were found to be treated for salvage indications. Biochemical failure was defined as prostate-specific antigen (PSA) of 0.2 ng/mL or greater above nadir with another PSA increase or the initiation of salvage ADT. Progression-free survival (PFS) was defined as the absence of biochemical failure, continued PSA rise despite salvage therapy, initiation of systemic therapy, clinical progression, or distant failure. Multivariate-adjusted Cox proportional hazards modeling was performed to determine which factors predict PFS. Results: Low-, intermediate-, and high-risk patients made up 10%, 24%, and 66% of patients, respectively. The mean RT dose was 68 Gy. Twenty-four percent of patients received concurrent ADT (cADT). Regional pelvic nodes were treated in 16% of patients. With a median follow-up of 3 years, the 3-year PFS was 4.0 years for cADT vs. 3.4 years for cADT patients (p = 0.22). Multivariate analysis showed that concurrent ADT (p = 0.05), Gleason score (p < 0.001), and pre-RT PSA (p = 0.03) were independent predictors of PFS. When patients were stratified by risk group, the benefits of cADT (hazard ratio, 0.65; p = 0.046) were significant only for high-risk patients. Conclusions: This retrospective study showed a PFS benefit of concurrent ADT during salvage prostate RT. This benefit was observed only in high-risk patients.

  8. DJ-1 and androgen receptor immunohistochemical expression in prostatic carcinoma: A possible role in carcinogenesis

    International Nuclear Information System (INIS)

    Background and Aim: Androgen plays a fundamental role in the growth and differentiation of prostate. Androgen receptor (AR) expression may represent a potential marker of prognosis in prostate cancer. However, there have been variable results regarding its ability to predict clinical progression. Despite the oncogenic properties of DJ-1, its significance in prostate cancer development and progression is not well understood. This research shed some light on the possible role of immunohistochemical expression of DJ-1 in clinically localized prostatic carcinoma in relation to the established role of AR and other clinico pathologic parameters. Materials and Methods: The immunohistochemical expression of AR and DJ-1 was evaluated in 129 samples including benign hyperplasia (n = 60) and prostatic carcinoma (n = 69). Results: The mean value of AR immunostaining was significantly higher in prostatic carcinomas than in benign hyperplasia (P = 0.001). A significant inverse correlation was found between AR immunostaining and the grade of prostatic carcinomas. A significantly higher median DJ-1 score was found in prostatic carcinoma than in benign hyperplasia (P = 0.0001). There was a significant direct correlation between AR and DJ-1 score (P = 0.0001). AR is more sensitive in predicting prostatic carcinoma than DJ-1 but DJ-1 is more specific than AR. Conclusion: AR nuclear expression was consistently present in benign and adenocarcinoma epithelium. But, there may be limited clinical use for AR expression in localized carcinoma due to its constant heterogeneity. DJ-1 with its oncogenic properties, specificity for prostatic carcinoma and homogenous expression gives an ideal complementary role to AR in the detection and treatment of prostatic carcinomas.

  9. Expression of novel genes linked to the androgen-induced, proliferative shutoff in prostate cancer cells.

    Science.gov (United States)

    Geck, P; Szelei, J; Jimenez, J; Lin, T M; Sonnenschein, C; Soto, A M

    1997-01-01

    Androgens control cell numbers in the prostate through three separate pathways: (a) inhibition of cell death, (b) induction of cell proliferation (Step-1) and (c) inhibition of cell proliferation (Step-2, proliferative shutoff). The mechanisms underlying these phenomena are incompletely understood. The human prostate carcinoma LNCaP variants express these pathways as follows: LNCaP-FGC express both steps, LNCaP-LNO expresses Step-2, LNCaP-TAC expresses Step-1, and LNCaP-TJA cells express neither step. These cells facilitated the search for mediators of the androgen-induced proliferative shutoff pathway. Androgen exposure for 24 h or longer induced an irreversible proliferative shutoff in LNCaP-FGC cells. The Wang and Brown approach for identifying differentially expressed mRNAs was used to search for mediators of Step-2. Ten unique inserts were identified and from those ten, three genes were further studied. The basal expression of these genes in shutoff-negative variants was not affected by androgen exposure. They were induced by androgens in shutoff-positive LNCaP variants and the androgen receptor-transfected, shutoff-positive, MCF7-AR1 cells. These genes were induced only in the range of androgen concentrations that elicited the shutoff response. Time course analysis showed that their induction precedes the commitment point by 12-18 h. In addition, they were expressed in the normal prostate during proliferative shutoff. These features suggest that the candidate genes have a role in the regulation cascade for proliferative shutoff.

  10. Role of the HSP90-associated cochaperone p23 in enhancing activity of the androgen receptor and significance for prostate cancer.

    Science.gov (United States)

    Reebye, Vikash; Querol Cano, Laia; Lavery, Derek N; Brooke, Greg N; Powell, Sue M; Chotai, Deepa; Walker, Marjorie M; Whitaker, Hayley C; Wait, Robin; Hurst, Helen C; Bevan, Charlotte L

    2012-10-01

    Prostate tumor growth initially depends on androgens, which act via the androgen receptor (AR). Despite androgen ablation therapy, tumors eventually progress to a castrate-resistant stage in which the AR remains active. The mechanisms are poorly understood but it may be that changes in levels or activity of AR coregulators affect trafficking and activation of the receptor. A key stage in AR signaling occurs in the cytoplasm, where unliganded receptor is associated with the heat shock protein (HSP)90 foldosome complex. p23, a key component of this complex, is best characterized as a cochaperone for HSP90 but also has HSP90-independent activity and has been reported as having differential effects on the activity of different steroid receptors. Here we report that p23 increases activity of the AR, and this appears to involve steps both in the cytoplasm (increasing ligand-binding capacity, possibly via direct interaction with AR) and the nucleus (enhancing AR occupancy at target promoters). We show, for the first time, that AR and p23 can interact, perhaps directly, when HSP90 is not present in the same complex. The effects of p23 on AR activity are at least partly HSP90 independent because a mutant form of p23, unable to bind HSP90, nevertheless increases AR activity. In human prostate tumors, nuclear p23 was higher in malignant prostate cells compared with benign/normal cells, supporting the utility of p23 as a therapeutic target in prostate cancer.

  11. A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors

    International Nuclear Information System (INIS)

    Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~ 25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P < 0.01) and increased expression of ER-β target TNF-α (P < 0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization. - Highlights: • BP with benzopyran core of genistein was identified for ER-β selective action. • BP was 14-times more potent than genistien in targeting prostate cancer cells. • It behaved as a potent ER-β agonist and ER-α antagonist in gene reporter assays. • BP's anti-proliferative action was inhibited significantly in ER-β deficient cells. • BP — a unique lead

  12. A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Rajeev; Verma, Vikas; Sharma, Vikas; Jain, Ashish; Singh, Vishal [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Sarswat, Amit [Division of Medicinal & Process Chemistry, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Maikhuri, Jagdamba P. [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Sharma, Vishnu L. [Division of Medicinal & Process Chemistry, CSIR—Central Drug Research Institute, Lucknow 226 031 (India); Gupta, Gopal, E-mail: g_gupta@cdri.res.in [Division of Endocrinology, CSIR—Central Drug Research Institute, Lucknow 226 031 (India)

    2015-03-15

    Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~ 25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P < 0.01) and increased expression of ER-β target TNF-α (P < 0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization. - Highlights: • BP with benzopyran core of genistein was identified for ER-β selective action. • BP was 14-times more potent than genistien in targeting prostate cancer cells. • It behaved as a potent ER-β agonist and ER-α antagonist in gene reporter assays. • BP's anti-proliferative action was inhibited significantly in ER-β deficient cells. • BP — a unique lead

  13. Androgen deprivation causes truncation of the C-terminal region of androgen receptor in human prostate cancer LNCaP cells.

    Science.gov (United States)

    Harada, Naoki; Inoue, Kaoru; Yamaji, Ryoichi; Nakano, Yoshihisa; Inui, Hiroshi

    2012-06-01

    The androgen receptor (AR) acts as a ligand-dependent transcription factor, whereas mutant AR lacking the C-terminal ligand-binding domain functions in a ligand-independent manner. In the present study we report that the C-terminal truncated AR, which we named AR-NH1 (the N-terminal fragment of AR cleaved in the neighborhood of helix 1 of the ligand-binding domain), is produced in LNCaP prostatic carcinoma cells. The AR-NH1 of ~90 kDa was observed in an androgen-independent LNCaP subline and was further accumulated by the proteasome inhibitor MG132. MG132 treatment caused the accumulation of AR-NH1 even in parent LNCaP cells. AR-NH1 was produced in the absence of ligand or in the presence of the AR antagonist bicalutamide, whereas AR agonists suppressed its production. AR-NH1 was detected with different AR antibodies recognizing amino acid residues 1-20 and 300-316 and was also generated from exogenous AR. Both siRNA-mediated AR knockdown and treatment with a serine protease inhibitor (4-(2-aminoethyl)-benzenesulfonyl fluoride) reduced AR-NH1 levels. According to the predicted cleavage site (between amino acid residues 660-685) and its nuclear localization, it is assumed that AR-NH1 functions as a constitutively active transcription factor. These data suggest that AR-NH1 is produced under hormone therapy and contributes to the development of castration-resistant prostate cancer due to its ligand-independent transcriptional activity.

  14. Protein kinase D1 (PKD1) influences androgen receptor (AR) function in prostate cancer cells

    International Nuclear Information System (INIS)

    Protein kinase D1 (PKD1), founding member of PKD protein family, is down-regulated in advanced prostate cancer (PCa). We demonstrate that PKD1 and androgen receptor (AR) are present as a protein complex in PCa cells. PKD1 is associated with a transcriptional complex which contains AR and promoter sequence of the Prostate Specific Antigen (PSA) gene. Ectopic expression of wild type PKD1 and the kinase dead mutant PKD1 (K628W) attenuated the ligand-dependent transcriptional activation of AR in prostate cancer cells and yeast cells indicating that PKD1 can affect AR transcription activity, whereas knocking down PKD1 enhanced the ligand-dependent transcriptional activation of AR. Co-expression of kinase dead mutant with AR significantly inhibited androgen-mediated cell proliferation in both LNCaP and DU145 PC cells. Our data demonstrate for the first time that PKD1 can influence AR function in PCa cells

  15. Combination of external irradiation and androgen suppression for prostate cancer: Facts and questions; Radiotherapie et hormonotherapie pour le cancer de la prostate: acquis et interrogations

    Energy Technology Data Exchange (ETDEWEB)

    Bolla, M.; Fourneret, P.; Beneyton, V.; Tessier, A.; Jover, F.; Verry, C. [Pole de cancerologie, clinique universitaire de cancerologie-radiotherapie, centre hospitalier universitaire de Grenoble, 38 - Grenoble (France)

    2010-10-15

    The combination of radiotherapy and androgen suppression with luteinizing hormone releasing hormone agonist is mainly devoted to locally advanced prostate cancer and intermediate or poor risk localized prostate cancer. They are based on phase III randomized trials which have shown that for locally advanced prostate cancer, a four-month complete androgen blockade initiated two months prior radiotherapy and stopped at the completion of radiotherapy increased overall survival in patients with Gleason scores 2-6, meanwhile, an adjuvant long-term androgen suppression (2.5 to three years) improved significantly the overall survival. Complete androgen blockade with a four to six months duration, combined with external irradiation, enhanced the overall survival in patients with intermediate or poor risk localized prostate cancer. (authors)

  16. Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer.

    Directory of Open Access Journals (Sweden)

    Steven Kregel

    Full Text Available Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR, has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5 expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways.

  17. Is neoadjuvant androgen deprivation therapy beneficial in prostate cancer treated with definitive radiotherapy?

    Energy Technology Data Exchange (ETDEWEB)

    Eom, Keun Yong; Ha, Sung W.; Lee, Eun Sik; Kwak, Cheol [Seoul National University College of Medicine, Seoul (Korea, Republic of); Lee, Sang Eun [Dept.of Urology, Seoul National University Bundang Hospital, Seongam (Korea, Republic of)

    2014-12-15

    To determine whether neoadjuvant androgen deprivation therapy (NADT) improves clinical outcomes in patients with prostate cancer treated with definitive radiotherapy. We retrospectively reviewed medical records of 201 patients with prostate cancer treated with radiotherapy between January 1991 and December 2008. Of these, 156 patients with more than 3 years of follow-up were the subjects of this study. The median duration of follow-up was 91.2 months. NADT was given in 103 patients (66%) with median duration of 3.3 months (range, 1.0 to 7.7 months). Radiation dose was escalated gradually from 64 Gy to 81 Gy using intensity-modulated radiotherapy technique. Biochemical relapse-free survival (BCRFS) and overall survival (OS) of all patients were 72.6% and 90.7% at 5 years, respectively. BCRFS and OS of NADT group were 79.5% and 89.8% at 5 years and those of radiotherapy alone group were 58.8% and 92.3% at 5 years, respectively. Risk group (p = 0.010) and radiation dose > or =70 Gy (p = 0.017) affected BCRFS independently. NADT was a significant prognostic factor in univariate analysis, but not in multivariate analysis (p = 0.073). Radiation dose > or =70 Gy was only an independent factor for OS (p = 0.007; hazard ratio, 0.261; 95% confidence interval, 0.071-0.963). NADT prior to definitive radiotherapy did not result in significant benefit in terms of BCRFS and OS. NADT should not be performed routinely in the era of dose-escalated radiotherapy.

  18. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines.

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V

    2016-01-01

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors. PMID:27623747

  19. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V.

    2016-01-01

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors. PMID:27623747

  20. Refinement of the androgen response element based on ChIP-Seq in androgen-insensitive and androgen-responsive prostate cancer cell lines.

    Science.gov (United States)

    Wilson, Stephen; Qi, Jianfei; Filipp, Fabian V

    2016-09-14

    Sequence motifs are short, recurring patterns in DNA that can mediate sequence-specific binding for proteins such as transcription factors or DNA modifying enzymes. The androgen response element (ARE) is a palindromic, dihexameric motif present in promoters or enhancers of genes targeted by the androgen receptor (AR). Using chromatin immunoprecipitation sequencing (ChIP-Seq) we refined AR-binding and AREs at a genome-scale in androgen-insensitive and androgen-responsive prostate cancer cell lines. Model-based searches identified more than 120,000 ChIP-Seq motifs allowing for expansion and refinement of the ARE. We classified AREs according to their degeneracy and their transcriptional involvement. Additionally, we quantified ARE utilization in response to somatic copy number amplifications, AR splice-variants, and steroid treatment. Although imperfect AREs make up 99.9% of the motifs, the degree of degeneracy correlates negatively with validated transcriptional outcome. Weaker AREs, particularly ARE half sites, benefit from neighboring motifs or cooperating transcription factors in regulating gene expression. Taken together, ARE full sites generate a reliable transcriptional outcome in AR positive cells, despite their low genome-wide abundance. In contrast, the transcriptional influence of ARE half sites can be modulated by cooperating factors.

  1. T3 prostate cancer: induction androgen suppression combined with prostatectomy does not surpass definitive irradiation

    International Nuclear Information System (INIS)

    (63 vs 67; p<0.01). The median PSA baselines were 16 vs. 39 ng/ml for the irradiated and prostatectomized patients, respectively. In univariate comparison, the freedom from biochemical relapse rate at 3 years was 41% for irradiated patients and 23% for those treated by hormones combined with surgery (p<0.05). Severe complications arose in 3 surgically treated patients (bladder neck contracture) and one irradiated patient (grade 3 cystitis). In a multivariate regression model controlling for the prognostic factors of baseline PSA, age, clinical substage, Gleason score, and treatment modality (induction androgen suppression + prostatectomy vs. RT) only low baseline PSA independently predicted improved BNED survival (p=0.04). CONCLUSIONS: For men with T3 prostate tumors, induction hormones combined with surgery were associated with more severe complications and an inferior rate of freedom from biochemical relapse when compared to conventional irradiation. Although multivariate analysis did not identify treatment with radiotherapy as an independent predictor of improved BNED, it should be underscored that negative nodal status was only pathologically established among the patients treated with surgery. More innovative strategies such as conformal irradiation (either alone or combined with androgen ablation) and radiation dose escalation should be pursued to optimize outcome for this unfavorable group of patients

  2. Supraadditive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation

    International Nuclear Information System (INIS)

    Purpose: Androgen ablation is often combined with radiation in the treatment of patients with prostate cancer, yet, the optimal sequencing and the mechanisms governing the interaction are not understood. The objectives were to determine if cell killing via apoptosis is enhanced when the combined treatment is administered and to define the relationship of changes in this form of cell killing to tumor volume growth delay. Materials and Methods: Dunning R3327-G rat prostate tumors, grown in the flanks of Copenhagen rats, were used at a volume of approximately 1 cc. Androgen ablation was initiated by castration, and androgen restoration was achieved with 0.5 cm silastic tube implants containing testosterone. 60Co was used for irradiation. The terminal deoxynucleotidyl transferase (TUNEL) histochemical assay was used to quantify apoptosis. Results: Tumors from intact and castrate unirradiated control rats had average apoptotic indices (percent of apoptotic cells) of 0.4 and 1.0%, respectively. The apoptotic index varied only slightly over time (3 h to 28 days) after castration (range 0.75-1.43%). Irradiation of intact rats to 7 Gy resulted in a peak apoptotic response at 6 h of 2.3%. A supra additive apoptotic response was seen when castration was initiated 3 days prior to 7 Gy radiation, with peak levels of about 10.1%. When the radiation was administered at increasing times beyond 3 days after castration, the apoptotic response gradually diminished and was back to levels seen in intact rats by 28 days after castration. Tumor volume growth delay studies were consistent with, but not conclusive proof of, a supra additive effect when the combination was used. Discussion: A supra additive apoptotic response was seen when androgen ablation and radiation were used to treat androgen sensitive R3327-G rat prostate tumors. This supra additive effect was dependent on the timing of the two treatments. Further studies are required to more fully define the optimal timing and

  3. Do androgens control the uptake of {sup 18}F-FDG, {sup 11}C-choline and {sup 11}C-acetate in human prostate cancer cell lines?

    Energy Technology Data Exchange (ETDEWEB)

    Emonds, Kimy M.; Nuyts, Johan; Mortelmans, Luc [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); Swinnen, Johannes V.; Vanderhoydonc, Frank [K.U. Leuven, Laboratory for Experimental Medicine and Endocrinology, Department of Experimental Medicine, Leuven (Belgium); Weerden, Wytske M. van [Erasmus University Rotterdam, Department of Experimental Urology, Josephine Nefkens Institute, Rotterdam (Netherlands); Mottaghy, Felix M. [University Hospital Gasthuisberg Leuven, Department of Nuclear Medicine, Leuven (Belgium); University Hospital Aachen, Department of Nuclear Medicine, Aachen (Germany); Maastricht University Medical Center, Department of Nuclear Medicine, Maastricht (Netherlands)

    2011-10-15

    The aim of this study was to evaluate the impact of androgen ablation therapy in different prostate cancer (PCa) cell lines - reflecting different stages of the disease - on {sup 18}F-fluorodeoxyglucose (FDG), {sup 11}C-choline and {sup 11}C-acetate uptake. Uptake experiments were performed in androgen-sensitive (LNCaP, PC346C) and independent cell lines (22Rv1, PC346DCC, PC-3) as well as in a benign prostatic hyperplasia (BPH-1) cell line. Tracer uptake was assessed under androgen ablation. Results of the cancer cell lines were normalized to those of BPH-1. To evaluate the effect of androgen on the uptake of {sup 18}F-FDG, {sup 11}C-choline and {sup 11}C-acetate in PCa cell lines, 10{sup -8}M R1881, 10{sup -10}M R1881, the combination of 10{sup -10}M R1881 plus 10{sup -6}M Casodex or 10{sup -6}M Casodex alone were added in parallel cell cultures 1 day before uptake experiments. Uptake in androgen-supplemented cell cultures was compared to the uptake under androgen deprivation. Uptake was corrected for cell number using protein content. Compared to BPH-1, a higher {sup 18}F-FDG uptake was observed only in PC346C cells, whereas a higher {sup 11}C-choline and markedly increased {sup 11}C-acetate uptake was seen in all cancer cell lines. Androgens significantly modulated the uptake of {sup 18}F-FDG in LNCaP, PC346C and 22Rv1 cells, and of {sup 11}C-choline in the PC346C and 22Rv1 cell line. No androgenic effect on {sup 11}C-choline and {sup 18}F-FDG uptake was observed in PC-3 and PC346DCC cells. {sup 11}C-Acetate uptake was independent of androgen status in all PCa cell lines studied. {sup 18}F-FDG uptake in PCa cell lines showed the highest variability and strongest androgen effect, suggesting its poor potential for metabolic imaging of advanced PCa. In contrast to {sup 18}F-FDG and {sup 11}C-choline, {sup 11}C-acetate uptake was unaffected by androgens and thus {sup 11}C-acetate seems best for monitoring PCa progression. (orig.)

  4. Pre-treatment nomogram for biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for clinically localised prostate cancer

    OpenAIRE

    Parker, C C; Norman, A R; Huddart, R A; Horwich, A; Dearnaley, D P

    2002-01-01

    Phase III studies have demonstrated the clinical benefit of adding neo-adjuvant androgen deprivation to radical radiotherapy for clinically localised prostate cancer. We have developed a nomogram to describe the probability of PSA control for patients treated in this way. Five hundred and seventeen men with clinically localised prostate cancer were treated with 3–6 months of neo-adjuvant androgen deprivation and radical radiotherapy (64 Gy in 32#) between 1988 and 1998. Median presenting PSA ...

  5. Disruption of androgen and estrogen receptor activity in prostate cancer by a novel dietary diterpene carnosol: implications for chemoprevention

    OpenAIRE

    Jeremy J Johnson; Syed, Deeba N.; Suh, Yewseok; Heren, Chenelle R.; Saleem, Mohammad; Siddiqui, Imtiaz A.; Mukhtar, Hasan

    2010-01-01

    Emerging data is suggesting that estrogens, in addition to androgens, may also be contributing to the development of prostate cancer (PCa). In view of this notion agents that target estrogens, in addition to androgens, may be a novel approach for PCa chemoprevention and treatment. Thus, the identification and development of non-toxic dietary agents capable of disrupting androgen receptor (AR) in addition to estrogen receptor (ER) could be extremely useful in the management of PCa. Through mol...

  6. Sequential Androgen Receptor Pathway Inhibitor in Prostate Cancer: Piling-Up The Benefits or a Case for Cross-Resistance?

    OpenAIRE

    Bertrand Tombal

    2014-01-01

    In the last 10 years, there has been accumulating evidence that, even in a low serum testosterone environment, the androgen receptor (AR) remains the main driver of prostate cancer progression. This has led to the discovery and clinical development of new anti-androgens and androgen biosynthesis inhibitors. Enzalutamide and abiraterone acetate are the lead compounds of this new generation of agents, but multiple other agents are on their way. Because they both target the ligand-dependent regu...

  7. Do androgen deprivation drugs affect the immune cross-talk between mononuclear and prostate cancer cells?

    Science.gov (United States)

    Salman, Hertzel; Bergman, Michael; Blumberger, Naava; Djaldetti, Meir; Bessler, Hanna

    2014-02-01

    The aim of the study was to examine the effect of androgen deprivation drugs, i.e. leuprolide and bicalutamide on the immune cross-talk between human peripheral blood mononuclear cells (PBMC) and cells from PC-3 and LNCaP human prostate cancer lines. PBMC, PC-3 and LNCaP were separately incubated without and with two androgen-deprivation drugs, i.e. leuprolide and bicalutamide, and the secretion of IL-1β, IL-6, IL-1ra and IL-10 was examined. In addition, the effect of both drugs on the production of those cytokines was carried out after 24 hours incubation of PBMC with both types of cancer cells. Leuprolide or bicalutamide did not affect the production of the cytokines by PBMC or by the prostate cancer cells from the two lines. Incubation of PBMC with PC-3 or LNCaP cells caused increased production of IL-1β, IL-6 and IL-10 as compared with PBMC incubated without malignant cells. While 10(-7) M and 10(-8) M of leuprolide caused a decreased secretion of IL-1β by PBMC previously incubated with prostate cancer cells without the drug, bicalutamide did not affect this PBMC activity at any drug concentration. This observation suggests the existence of an additional mechanism explaining the effect of androgen deprivation therapy in prostate cancer patients.

  8. Influence of radiotherapy on node-positive prostate cancer treated with androgen ablation

    International Nuclear Information System (INIS)

    Purpose: Patients with node-positive prostate cancer that is regionally localized (T1-4, N1-3, M0) have a relatively poor prognosis when a single-treatment modality such as radical surgery, definitive radiotherapy, or androgen ablation is used. While promising results using radical surgery and androgen ablation have been reported, there are no data to support an analogous approach using local radiotherapy and androgen ablation. In this retrospective review, the outcome after local radiotherapy and early androgen ablation (XRT/HORM) was compared to early androgen ablation alone (HORM). Methods and Materials: Between 1984 and 1992 there were 181 patients treated with HORM and 27 patients treated with XRT/HORM at the University of Texas M. D. Anderson Cancer Center. The nodal status of all patients was established pathologically by lymph node dissection, which was terminated after frozen section confirmation of involvement. In the majority of cases androgen ablation was by orchiectomy. The median dose to the prostate in XRT/HORM group was 66 Gy. The median follow-up was 45 months; 49 months for the HORM group and 25 months for the XRT/HORM group. Results: The distribution of prognostic factors between the HORM and XRT/HORM groups was similar, with the exception of tumor grade. There was a significantly larger proportion of high grade tumors in the HORM group. In terms of actuarial disease outcome, at 4 years the results of patients in the HORM group were significantly worse, including a rising prostate specific antigen (PSA) of 53%, any disease progression of 32%, a rising PSA or disease progression of 55%, and local progression of 22%. None of the patients in the XRT/HORM group failed biochemically or clinically. To determine the impact of grade on these findings, the analyses were repeated, using only those with grade 2 tumors. A similar pattern was evidenced with significantly worse actuarial outcome at 4 years for the HORM group using the endpoints of a rising PSA

  9. Androgen-stimulated UDP-glucose dehydrogenase expression limits prostate androgen availability without impacting hyaluronan levels

    OpenAIRE

    Wei, Qin; Galbenus, Robert; Raza, Ashraf; Ronald L. Cerny; Simpson, Melanie A.

    2009-01-01

    UDP-glucose dehydrogenase (UGDH) oxidizes UDP-glucose to UDP-glucuronate, an essential precursor for production of hyaluronan (HA), proteoglycans, and xenobiotic glucuronides. High levels of HA turnover in prostate cancer are correlated with aggressive progression. UGDH expression is high in the normal prostate even though HA accumulation is virtually undetectable. Thus, its normal role in the prostate may be to provide precursors for glucuronosyltransferase enzymes, which inactivate and solu...

  10. ANDROGEN REGULATION OF PROSTATIC STEROID BINDING PROTEIN GENE TRANSCRIPTION

    Institute of Scientific and Technical Information of China (English)

    ZHANGYong-Lian; ZHOUZong-Xun; ZHANGYou-Duan; PARKERMalcolmG

    1989-01-01

    Prostatic steroid binding protein (PSBP) is a major protein secreted in the rat ventral prostate (V.P.) and also one of the components in seminal fluid, The potential importance of this protein in male fertility emerged from its ability of binding cholesterol which might modulate the proportion of phospholipids and cholesterol in sperm making it suitable

  11. The study of the androgen receptor profile and changes of level of serum testosterone in human prostatic cancer

    International Nuclear Information System (INIS)

    The androgen receptors in biopsy specimens of 22 cases of human prostatic cancer (PC) were studied by radioligand binding assay. The cytoplasmic androgen receptor (AcR) and nuclear androgen receptor (AnR) densities were 305.70 +- 461.68 and 363.04 +- 391.44 pmol/g protein respectively, both were significantly higher than those of 36 benign prostatic hypertrophy (BPH) and 9 normal prostate (NP). Among the prostatic cancers, the AnR/AcR ratios were significantly different between metastatic and primary cancers. This result suggested that there might be migration of AR from nucleus to cytosol in the process of metastasis. The serum testosterone studied by RIA method are significantly lower than that of BPH and NP. Thawmounted autoradiography demonstrated that AR were mainly located in epithelial cells of the glandular tissue of prostate

  12. Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells

    DEFF Research Database (Denmark)

    Griend, Donald J Vander; Antony, Lizamma; Dalrymple, Susan L;

    2009-01-01

    There are quantitative and/or qualitative mechanisms allowing androgen receptor (AR) growth signaling in androgen ablation refractory prostate cancer cells. Regardless of the mechanism, agents that deplete AR protein expression prevent such AR growth signaling. Thapsigargin (TG) is a highly cell......-penetrant sequiterpene-lactone that once inside cells inhibits (IC(50), approximately 10 nmol/L) critically important housekeeping SERCA 2b calcium pumps in the endoplasmic reticulum. Using a series of five genetically diverse androgen ablation refractory human prostate cancer lines (LNCaP, LAPC-4, VCaP, MDA-PCa-2b, and......-specific proteases, such as prostate-specific antigen and prostate-specific membrane antigen, or cancer-specific proteases, such as fibroblast activation protein, so that toxicity of these prodrugs is selectively targeted to metastatic sites of prostate cancer. Based on these results, these prodrugs are undergoing...

  13. TCTP is an androgen-regulated gene implicated in prostate cancer.

    Directory of Open Access Journals (Sweden)

    Mari Kaarbø

    Full Text Available TCTP has been implicated in a plethora of important cellular processes related to cell growth, cell cycle progression, malignant transformation and inhibition of apoptosis. In addition to these intracellular functions, TCTP has extracellular functions and plays an important role in immune cells. TCTP expression was previously shown to be deregulated in prostate cancer, but its function in prostate cancer cells is largely unknown. Here we show that TCTP expression is regulated by androgens in LNCaP prostate cancer cells in vitro as well as human prostate cancer xenografts in vivo. Knockdown of TCTP reduced colony formation and increased apoptosis in LNCaP cells, implicating it as an important factor for prostate cancer cell growth. Global gene expression profiling in TCTP knockdown LNCaP cells showed that several interferon regulated genes are regulated by TCTP, suggesting that it may have a role in regulating immune function in prostate cancer. In addition, recombinant TCTP treatment increased colony formation in LNCaP cells suggesting that secreted TCTP may function as a proliferative factor in prostate cancer. These results suggest that TCTP may have a role in prostate cancer development.

  14. Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Mark Schrader

    2012-09-01

    Full Text Available Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR. A putative mechanism allowing prostate cancer (PCa cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD. Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa.

  15. Familial prostate cancer: outcome following radiation therapy with or without adjuvant androgen ablation

    International Nuclear Information System (INIS)

    Purpose: To compare the outcome of familial versus sporadic prostate carcinoma after definitive external radiation. Methods and Materials: Between 1987 and 1996, 1214 men with clinically localized prostate cancer (T1-T4, N0/NX, M0) received definitive radiation therapy in our department. By retrospective review of charts and questioning of patients, a record on the presence or absence of prostate cancer in a first degree relative was obtained in 1164 men. Univariate and multivariate analysis was performed on these cases with relapse or rising prostate-specific antigen (PSA), local recurrence, metastasis, and survival as endpoints. Results: Familiar prostate cancer was present in 148 of 1164 men (13%). Men with familial disease were slightly but significantly younger (mean 66 years) at diagnosis than those with sporadic disease (mean 68 years) (p = 0.02). Apart from this there were no significant differences between the two groups in T-stage, Gleason score, pretreatment PSA levels, DNA ploidy, or serum testosterone levels. There were no significant differences in treatment parameters including radiation dose and the use of adjuvant androgen ablation. With a median follow-up of 42 months, there was no difference in freedom from relapse or rising PSA at 6 years between those with a family history (54%) and those without a family history (58%) (p = 0.171). Likewise there was no difference between the two groups when local recurrence or metastasis was the endpoint. Multiple subgroup analyses (younger and older; T1/T2 and T3; low Gleason and high Gleason; no androgen ablation and androgen ablation; race) failed to reveal any differences in outcome in any category between familial and sporadic disease. Among patients with a rising post-treatment PSA profile, PSA doubling times were similar in those with sporadic and familial disease. Conclusions: This study provides no evidence for any substantial difference between familial and sporadic prostate cancer either in

  16. Combined brachytherapy and external beam radiotherapy without adjuvant androgen deprivation therapy for high-risk prostate cancer

    International Nuclear Information System (INIS)

    To report the outcomes of patients treated with combined iodine-125 (I-125) brachytherapy and external beam radiotherapy (EBRT) for high-risk prostate cancer. Between 2003 and 2009, I-125 permanent prostate brachytherapy plus EBRT was performed for 206 patients with high-risk prostate cancer. High-risk patients had prostate-specific antigen ≥ 20 ng/mL, and/or Gleason score ≥ 8, and/or Stage ≥ T3. One hundred and one patients (49.0%) received neoadjuvant androgen deprivation therapy (ADT) but none were given adjuvant ADT. Biochemical failure-free survival (BFFS) was determined using the Phoenix definition. The 5-year actuarial BFFS rate was 84.8%. The 5-year cause-specific survival and overall survival rates were 98.7% and 97.6%, respectively. There were 8 deaths (3.9%), of which 2 were due to prostate cancer. On multivariate analysis, positive biopsy core rates and the number of high-risk factors were independent predictors of BFFS. The 5-year BFFS rates for patients in the positive biopsy core rate <50% and ≥50% groups were 89.3% and 78.2%, respectively (p = 0.03). The 5-year BFFS rate for patients with the any single high-risk factor was 86.1%, compared with 73.6% for those with any 2 or all 3 high-risk factors (p = 0.03). Neoadjuvant ADT did not impact the 5-year BFFS. At a median follow-up of 60 months, high-risk prostate cancer patients undergoing combined I-125 brachytherapy and EBRT without adjuvant ADT have a high probability of achieving 5-year BFFS

  17. Integrating diet and exercise into care of prostate cancer patients on androgen deprivation therapy.

    Science.gov (United States)

    Moyad, Mark A; Newton, Robert U; Tunn, Ulf W; Gruca, Damian

    2016-01-01

    Improved diagnosis and treatment regimens have resulted in greater longevity for men with prostate cancer. This has led to an increase in both androgen deprivation therapy (ADT) use and duration of exposure, and therefore to its associated adverse effects, such as sexual dysfunction, osteoporosis, reduced muscle mass, increased fat mass, and increased incidence of cardiovascular disease and type 2 diabetes. Given that the adverse effects of ADT are systemic, often debilitating, and difficult to treat, efforts continue in the development of new strategies for long-term management of prostate cancer. The PubMed database was searched to select trials, reviews, and meta-analyses in English using such search terms as "prostate cancer" and "androgen deprivation therapy", "cardiovascular risk", "lean body mass", "exercise", and "diet". The initial searches produced 379 articles with dates 2005 or more recent. Articles published after 2004 were favored. This review utilizes the latest data to provide a status update on the effects of exercise and diet on patients with prostate cancer, focusing on ADT-associated side effects, and it discusses the evidence for such interventions. Since the evidence of large-scale trials in patients with prostate cancer is missing, and an extrapolation of supporting data to all patient subgroups cannot be provided, individualized risk assessments remain necessary before the initiation of exercise and diet programs. Exercise, diet, and nutritional supplementation interventions have the potential to provide effective, accessible, and relatively inexpensive strategies for mitigating ADT-associated toxicities without introducing additional adverse effects. PMID:27574584

  18. Androgen receptor isoforms in human prostatic cancer tissue and LNCaP cell line

    Institute of Scientific and Technical Information of China (English)

    Shu-Jie XIA; Xiao-Da TANG; Qing-Zheng MA

    2001-01-01

    Aim: To investigate the androgen receptor (AR) isoform expressions in human prostatic cancer tissue and LNCaP cell line. Methods: With high resolution isoelectric focusing (IEF) method we demonstrated the different expressions of AR isoforms in human prostatic cancer tissues and LNCaP cell line. Results: Data were obtained from three prostatic cancer specimens and the LNCaP cell line. Three types of AR isoforms were detected with pI values at 6.5,6.0, and 5.3. For the 3 prostatic cancer specimens, 1 sample showed all the three types of AR isoforms, the second specimen expressed at 6.5 and 6.0, and the third failed to show any type of isoforms. The LNCaP cell line expressed all the three AR isoforms. Binding of 3H-dihydrotestosterone (3H-DHT) to these three isoforms was inhibited by the addition ofl00-fold excess of DHT or testosterone, while not by progesterone, oestradiol and diethylstilboestrol. Conclusion: The expression of AR isofonns is different in different prostate cancer tissues, which may be related to the difference in the effect of anti-androgen therapy in different patients.

  19. Effect of androgen deprivation therapy on cardiovascular risk factors in prostate cancer

    Directory of Open Access Journals (Sweden)

    Mahnaz Roayaei

    2013-01-01

    Full Text Available Background: Androgen deprivation is the basis of treatment for advanced stages of prostate cancer. Cardiovascular disease may be a risk factor for mortality in prostate cancer. Therefore, we decided to evaluate the effect of androgen deprivation therapy (ADT on the cardiovascular risk factors in patients with prostate cancer. Materials and Methods: In a cross-sectional study on 2011, 35 patients suffering from metastatic prostate cancer as candidates for ADT were enrolled. Serum levels of fasting blood sugar (FBS, triglyceride (TG and total cholesterol (TC were measured at the beginning and after the 5 th month of ADT. Results: The mean level of TG increased significantly from 130.82 ± 41.57 mg/dl to 150.05 ± 48.29 mg/dl (P < 0.012. Furthermore, serum level of TC increased from 197.62 ± 40.71 mg/dl to 212.54 ± 38.25 mg/dl, which is statistically significant (P < 0.001. A non-significant increase in the serum level of FBS from 96.74 ± 14.04 mg/dl to 99.17 ± 15.23 mg/dl was also seen (P = 0.27. Conclusion: ADT in prostate cancer may lead to an increase in TG and TC levels. In patients with a high risk of cardiovascular disease patient′s lipid profile should be considered during ADT.

  20. CH5137291, an androgen receptor nuclear translocation-inhibiting compound, inhibits the growth of castration-resistant prostate cancer cells.

    Science.gov (United States)

    Ishikura, Nobuyuki; Kawata, Hiromitsu; Nishimoto, Ayako; Nakamura, Ryo; Tsunenari, Toshiaki; Watanabe, Miho; Tachibana, Kazutaka; Shiraishi, Takuya; Yoshino, Hitoshi; Honma, Akie; Emura, Takashi; Ohta, Masateru; Nakagawa, Toshito; Houjo, Takao; Corey, Eva; Vessella, Robert L; Aoki, Yuko; Sato, Haruhiko

    2015-04-01

    Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH

  1. ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer.

    Science.gov (United States)

    Fizazi, Karim; Albiges, Laurence; Loriot, Yohann; Massard, Christophe

    2015-01-01

    Androgen deprivation therapy is the standard of care for patients with advanced hormone-sensitive prostate cancer. Despite an initial response, most patients progress to castration-resistant prostate cancer (CRPC). The realization that CRPC remains driven by androgen receptor (AR) signaling has formed the basis for a new generation of agents targeting the AR axis. Two of these agents, abiraterone acetate and enzalutamide, have been shown to prolong overall survival in patients with CRPC. Several other AR inhibitors are currently in development for the treatment of CRPC. The present article reviews ODM-201, a new-generation AR inhibitor with a unique molecular structure, in the treatment of CRPC. The design of an ongoing Phase III trial (ARAMIS) of ODM-201 in men with non-metastatic CRPC is also discussed, at a disease stage for which there is currently no approved treatment. PMID:26313416

  2. BAY 1024767 blocks androgen receptor mutants found in castration-resistant prostate cancer patients.

    Science.gov (United States)

    Sugawara, Tatsuo; Lejeune, Pascale; Köhr, Silke; Neuhaus, Roland; Faus, Hortensia; Gelato, Kathy A; Busemann, Matthias; Cleve, Arwed; Lücking, Ulrich; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Jung, Klaus; Stephan, Carsten; Haendler, Bernard

    2016-02-01

    Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.

  3. Effect of small molecules modulating androgen receptor (SARMs in human prostate cancer models.

    Directory of Open Access Journals (Sweden)

    Anna Tesei

    Full Text Available The management of hormone-refractory prostate cancer represents a major challenge in the therapy of this tumor, and identification of novel androgen receptor antagonists is needed to render treatment more effective. We analyzed the activity of two novel androgen receptor antagonists, (S-11 and (R-9, in in vitro and in vivo experimental models of hormone-sensitive or castration-resistant prostate cancer (CRPC. In vitro experiments were performed on LNCaP, LNCaP-AR, LNCaP-Rbic and VCaP human prostate cancer cells. Cytotoxic activity was assessed by SRB and BrdU uptake, AR transactivation by luciferase reporter assay and PSA levels by Real Time RT-PCR and ELISA assays. Cell cycle progression-related markers were evaluated by western blot. In vivo experiments were performed on SCID mice xenografted with cells with different sensitivity to hormonal treatment. In hormone-sensitive LNCaP and LNCaP-AR cells, the latter expressing high androgen receptor levels, (R-9 and (S-11 exhibited a higher cytotoxic effect compared to that of the reference compound ((R-bicalutamide, also in the presence of the synthetic androgen R1881. Furthermore, the cytotoxic effect produced by (R-9 was higher than that of (S-11 in the two hormone-resistant LNCaP-AR and VCaP cells. A significant reduction in PSA levels was observed after exposure to both molecules. Moreover, (S-11 and (R-9 inhibited DNA synthesis by blocking the androgen-induced increase in cyclin D1 protein levels. In vivo studies on the toxicological profile of (R-9 did not reveal the presence of adverse events. Furthermore, (R-9 inhibited tumor growth in various in vivo models, especially LNCaP-Rbic xenografts, representative of recurrent disease. Our in vitro results highlight the antitumor activity of the two novel molecules (R-9 and (S-11, making them a potentially attractive option for the treatment of CRPC.

  4. Dietary phenethyl isothiocyanate inhibition of androgen-responsive LNCaP prostate cancer cell tumor growth correlates with decreased angiogenesis

    Science.gov (United States)

    Phenethyl isothiocyanate (PEITC), found in certain cruciferous vegetables, has antitumor activity in several cancer models, including prostate cancer. In our xenograft model, dietary administration of PEITC (100-150 mg/kg/d) inhibited androgen-responsive LNCaP human prostate cancer cell tumor growth...

  5. LINE-1 ORF-1p functions as a novel androgen receptor co-activator and promotes the growth of human prostatic carcinoma cells.

    Science.gov (United States)

    Lu, Yinying; Feng, Fan; Yang, Yutao; Gao, Xudong; Cui, Jiajun; Zhang, Chuanfu; Zhang, Fan; Xu, Zhongxian; Qv, Jianhui; Wang, Chunping; Zeng, Zhen; Zhu, Yunfeng; Yang, Yongping

    2013-02-01

    Widespread interest in the mechanism of transcriptional regulation by the androgen receptor (AR) has been stimulated by the finding that AR signaling is critically important in the progression of human prostate cancers. Co-factors, the co-repressors, or the co-activators are responsible for the regulation of AR activation. The pro-oncogene human Long Interspersed Nucleotide acid Element-1 (LINE-1) encodes LINE-1 ORF-1p and plays important roles in the development and progression of several human carcinomas. In this study, the results showed that LINE-1 ORF-1p increased the AR transcriptional activity and in turn enhanced the expression of prostate specific antigen (PSA) in the presence of R1881. A physical protein-protein interaction between the AR signaling and the LINE-1 ORF-1p was identified by the immunoprecipitation assays and GST pull-down assays. Furthermore, LINE-1 ORF-1p would function as a novel AR positive co-regulator through modulating its cytoplasm/nucleus translocation and the recruitment to the androgen response element in the PSA gene promoter. Our date also showed that the LINE-1 ORF-1p promoted the proliferation and anchor-independent growth of LNCaP (ligand dependent) and PC-3 (ligand independent) human prostatic carcinoma cells. By investigating a novel role of the LINE-1 ORF-1p in the androgen/androgen receptor signaling pathway regulation, our study identifies that LINE-1 ORF-1p may be a novel AR co-regulator and molecular target for human prostate carcinoma therapy.

  6. Mathematical modeling of prostate cancer progression in response to androgen ablation therapy

    OpenAIRE

    Jain, Harsh Vardhan; Clinton, Steven K.; Bhinder, Arvinder; Friedman, Avner

    2011-01-01

    Prostate cancer progression depends in part on the complex interactions between testosterone, its active metabolite DHT, and androgen receptors. In a metastatic setting, the first line of treatment is the elimination of testosterone. However, such interventions are not curative because cancer cells evolve via multiple mechanisms to a castrate-resistant state, allowing progression to a lethal outcome. It is hypothesized that administration of antiandrogen therapy in an intermittent, as opposed...

  7. Choline Kinase Alpha as an Androgen Receptor Chaperone and Prostate Cancer Therapeutic Target

    Science.gov (United States)

    Asim, Mohammad; Massie, Charles E.; Orafidiya, Folake; Pértega-Gomes, Nelma; Warren, Anne Y.; Esmaeili, Mohsen; Selth, Luke A.; Zecchini, Heather I.; Luko, Katarina; Qureshi, Arham; Baridi, Ajoeb; Menon, Suraj; Madhu, Basetti; Escriu, Carlos; Lyons, Scott; Vowler, Sarah L.; Zecchini, Vincent R.; Shaw, Greg; Hessenkemper, Wiebke; Russell, Roslin; Mohammed, Hisham; Stefanos, Niki; Lynch, Andy G.; Grigorenko, Elena; D’Santos, Clive; Taylor, Chris; Lamb, Alastair; Sriranjan, Rouchelle; Yang, Jiali; Stark, Rory; Dehm, Scott M.; Rennie, Paul S.; Carroll, Jason S.; Griffiths, John R.; Tavaré, Simon; Mills, Ian G.; McEwan, Iain J.; Baniahmad, Aria; Tilley, Wayne D.; Neal, David E.

    2016-01-01

    Background: The androgen receptor (AR) is a major drug target in prostate cancer (PCa). We profiled the AR-regulated kinome to identify clinically relevant and druggable effectors of AR signaling. Methods: Using genome-wide approaches, we interrogated all AR regulated kinases. Among these, choline kinase alpha (CHKA) expression was evaluated in benign (n = 195), prostatic intraepithelial neoplasia (PIN) (n = 153) and prostate cancer (PCa) lesions (n = 359). We interrogated how CHKA regulates AR signaling using biochemical assays and investigated androgen regulation of CHKA expression in men with PCa, both untreated (n = 20) and treated with an androgen biosynthesis inhibitor degarelix (n = 27). We studied the effect of CHKA inhibition on the PCa transcriptome using RNA sequencing and tested the effect of CHKA inhibition on cell growth, clonogenic survival and invasion. Tumor xenografts (n = 6 per group) were generated in mice using genetically engineered prostate cancer cells with inducible CHKA knockdown. Data were analyzed with χ2 tests, Cox regression analysis, and Kaplan-Meier methods. All statistical tests were two-sided. Results: CHKA expression was shown to be androgen regulated in cell lines, xenografts, and human tissue (log fold change from 6.75 to 6.59, P = .002) and was positively associated with tumor stage. CHKA binds directly to the ligand-binding domain (LBD) of AR, enhancing its stability. As such, CHKA is the first kinase identified as an AR chaperone. Inhibition of CHKA repressed the AR transcriptional program including pathways enriched for regulation of protein folding, decreased AR protein levels, and inhibited the growth of PCa cell lines, human PCa explants, and tumor xenografts. Conclusions: CHKA can act as an AR chaperone, providing, to our knowledge, the first evidence for kinases as molecular chaperones, making CHKA both a marker of tumor progression and a potential therapeutic target for PCa. PMID:26657335

  8. The Early Effects of Rapid Androgen Deprivation on Human Prostate Cancer

    OpenAIRE

    Shaw, Greg L; Whitaker, Hayley; Corcoran, Marie; Dunning, Mark J.; Luxton, Hayley; Kay, Jonathan; Massie, Charlie E; Miller, Jodi L.; Lamb, Alastair D.; Ross-Adams, Helen; Russell, Roslin; Adam W Nelson; Eldridge, Matthew D.; Lynch, Andrew G.; Ramos-Montoya, Antonio

    2016-01-01

    The androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tum...

  9. Can Mathematical Models Predict the Outcomes of Prostate Cancer Patients Undergoing Intermittent Androgen Deprivation Therapy?

    Science.gov (United States)

    Everett, R. A.; Packer, A. M.; Kuang, Y.

    Androgen deprivation therapy is a common treatment for advanced or metastatic prostate cancer. Like the normal prostate, most tumors depend on androgens for proliferation and survival but often develop treatment resistance. Hormonal treatment causes many undesirable side effects which significantly decrease the quality of life for patients. Intermittently applying androgen deprivation in cycles reduces the total duration with these negative effects and may reduce selective pressure for resistance. We extend an existing model which used measurements of patient testosterone levels to accurately fit measured serum prostate specific antigen (PSA) levels. We test the model's predictive accuracy, using only a subset of the data to find parameter values. The results are compared with those of an existing piecewise linear model which does not use testosterone as an input. Since actual treatment protocol is to re-apply therapy when PSA levels recover beyond some threshold value, we develop a second method for predicting the PSA levels. Based on a small set of data from seven patients, our results showed that the piecewise linear model produced slightly more accurate results while the two predictive methods are comparable. This suggests that a simpler model may be more beneficial for a predictive use compared to a more biologically insightful model, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting. Nevertheless, both models are an important step in this direction.

  10. Differential effects of blueberry proanthocyanidins on androgen sensitive and insensitive human prostate cancer cell lines.

    Science.gov (United States)

    Schmidt, Barbara M; Erdman, John W; Lila, Mary Ann

    2006-01-18

    Blueberries are rich in health-promoting polyphenolic compounds including proanthocyanidins. The purpose of this study was to determine if proanthocyanidin-rich fractions from both wild and cultivated blueberry fruit have the same inhibitory effects on the proliferation of LNCaP, an androgen-sensitive prostate cancer cell line, and DU145, a more aggressive androgen insensitive prostate cancer cell line. When 20 microg/ml of a wild blueberry proanthocyanidin fraction (fraction 5) was added to LNCaP media, growth was inhibited to 11% of control with an IC50 of 13.3 microg/ml. Two similar proanthocyanidin-rich fractions from cultivated blueberries (fractions 4 and 5) at the same concentration inhibited LNCaP growth to 57 and 26% of control with an IC50 of 22.7 and 5.8 microg/ml, respectively. In DU145 cells, the only fraction that significantly reduced growth compared to control was fraction 4 from cultivated blueberries with an IC50 value of 74.4 microg/ml, indicating only minor inhibitory activity. Differences in cell growth inhibition of LNCaP and DU145 cell lines by blueberry fractions rich in proanthocyanidins indicate that blueberry proanthocyanidins have an effect primarily on androgen-dependant growth of prostate cancer cells. Possible molecular mechanisms for growth inhibition are reviewed. PMID:16399225

  11. Sequential maximum androgen blockade (MAB) in minimally symptomatic prostate cancer progressing after initial MAB:two case reports

    Institute of Scientific and Technical Information of China (English)

    Mohan Hingorani; Sanjay Dixit; Fahim Bashir; Mohammad Butt; Simon Hawkyard; Richard Khafagy; Andrew Robertson

    2014-01-01

    Te management of castrate-resistant prostate cancer progressing atfer maximum androgen blockade (MAB) has evolved in the last decade with the development of several novel therapeutic options. However, the initial therapeutic strategy in these patients usually involves withdrawal of anti-androgen that can be associated with biochemical response in approximately 20%of patients. Notably, we have observed evidence of sustained biochemical response in two patients following second-and third-line MAB using rechallenge schedule of previously administered anti-androgen atfer latent interval. hTe possibility of response following sequential MAB using the same anti-androgen agent has not yet been reported.

  12. Differential expression of androgen, estrogen, and progesterone receptors in benign prostatic hyperplasia.

    Science.gov (United States)

    Song, Lingmin; Shen, Wenhao; Zhang, Heng; Wang, Qiwu; Wang, Yongquan; Zhou, Zhansong

    2016-07-01

    This study aimed to identify the differential expression levels of androgen receptor (AR), estrogen receptors (ERα, ERβ), and progesterone receptor (PGR) between normal prostate and benign prostatic hyperplasia (BPH). The combination of immunohistochemistry, quantitative real-time reverse transcription polymerase chain reaction, and Western blotting assay was used to identify the distribution and differential expression of these receptors at the immunoactive biomarker, transcriptional, and protein levels between 5 normal human prostate tissues and 40 BPH tissues. The results were then validated in a rat model of BPH induced by testosterone propionate and estradiol benzoate. In both human and rat prostate tissues, AR was localized mainly to epithelial and stromal cell nuclei; ERα was distributed mainly to stromal cells, but not exclusively; ERβ was interspersed in the basal layer of epithelium, but sporadically in epithelial and stromal cells; PGR was expressed abundantly in cytoplasm of epithelial and stromal cells. There were decreased expression of ERα and increased expression of PGR, but no difference in the expression of ERβ in the BPH compared to the normal prostate of both human and rat. Increased expression of AR in the BPH compared to the normal prostate of human was observed, however, the expression of AR in the rat prostate tissue was decreased. This study identified the activation of AR and PGR and repression of ERα in BPH, which indicate a promoting role of AR and PGR and an inhibitory role of ERα in the pathogenesis of BPH. PMID:27483178

  13. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model.

    Science.gov (United States)

    Knuuttila, Matias; Yatkin, Emrah; Kallio, Jenny; Savolainen, Saija; Laajala, Teemu D; Aittokallio, Tero; Oksala, Riikka; Häkkinen, Merja; Keski-Rahkonen, Pekka; Auriola, Seppo; Poutanen, Matti; Mäkelä, Sari

    2014-08-01

    Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5α-dihydrotestosterone) at levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.

  14. 间歇性完全雄激素阻断治疗可延缓晚期前列腺癌雄激素非依赖状态的产生%Intermittent total androgen suppression may delay the androgen-independent state of advanced prostate cancer

    Institute of Scientific and Technical Information of China (English)

    兰卫华; 江军

    2004-01-01

    问题:间歇性与持续性完全雄激素阻断(total androgen blockade,TAB)或最大雄激素阻断(maximum androgen blockade,MAB)治疗比较,能否延缓前列腺癌雄激素非依赖状态的产生?近年来,一些实验研究及临床观察性试验表明,间歇性雄激素抑制(intermittent androgen suppression,IAS或intermittent androgen deprivation,IAD)较之于持续性雄激素抑制(continuous androgen suppression,CAS或continuous androgen deprivation,CAD)治疗,可能能够延缓前列腺癌雄激素非依赖状态的产生,延长生存期,提高生活质量,减少治疗相关的费用及副作用.但是尚无随机临床试验证实。目前正在进行的一项多中心Ⅲ期试验,报道了间歇性与持续性完全雄激素阻断治疗晚期前列腺癌患者3年进展率(雄激素非依赖状态)的比较。结果表明,间歇治疗组明显低于持续治疗组。

  15. Exercise improves quality of life in androgen deprivation therapy-treated prostate cancer: systematic review of randomised controlled trials.

    Science.gov (United States)

    Teleni, Laisa; Chan, Raymond J; Chan, Alexandre; Isenring, Elisabeth A; Vela, Ian; Inder, Warrick J; McCarthy, Alexandra L

    2016-02-01

    Men receiving androgen deprivation therapy (ADT) for prostate cancer (PCa) are likely to develop metabolic conditions such as diabetes, cardiovascular disease, abdominal obesity and osteoporosis. Other treatment-related side effects adversely influence quality of life (QoL) including vasomotor distress, depression, anxiety, mood swings, poor sleep quality and compromised sexual function. The objective of this study was to systematically review the nature and effects of dietary and exercise interventions on QoL, androgen deprivation symptoms and metabolic risk factors in men with PCa undergoing ADT. An electronic search of CINAHL, CENTRAL, Medline, PsychINFO and reference lists was performed to identify peer-reviewed articles published between January 2004 and December 2014 in English. Eligible study designs included randomised controlled trials (RCTs) with pre- and post-intervention data. Data extraction and assessment of methodological quality with the Cochrane approach was conducted by two independent reviewers. Seven exercise studies were identified. Exercise significantly improved QoL, but showed no effect on metabolic risk factors (weight, waist circumference, lean or fat mass, blood pressure and lipid profile). Two dietary studies were identified, both of which tested soy supplements. Soy supplementation did not improve any outcomes. No dietary counselling studies were identified. No studies evaluated androgen-deficiency symptoms (libido, erectile function, sleep quality, mood swings, depression, anxiety and bone mineral density). Evidence from RCTs indicates that exercise enhances health- and disease-specific QoL in men with PCa undergoing ADT. Further studies are required to evaluate the effect of exercise and dietary interventions on QoL, androgen deprivation symptoms and metabolic risk factors in this cohort. PMID:26584972

  16. Aberrant activation of the androgen receptor by NF-kappaB2/p52 in prostate cancer cells.

    Science.gov (United States)

    Nadiminty, Nagalakshmi; Lou, Wei; Sun, Meng; Chen, Jun; Yue, Jiao; Kung, Hsing-Jien; Evans, Christopher P; Zhou, Qinghua; Gao, Allen C

    2010-04-15

    Prostate cancer initiation and progression are uniquely dependent on the androgen receptor (AR). Even when the cancer progresses to a castration-resistant stage, AR signaling remains active via a variety of mechanisms. In the present study, we showed that NF-kappaB/p52 can activate the AR, resulting in increased transactivation of AR-responsive genes, such as PSA and NKX3.1, in a ligand-independent manner. NF-kappaB2/p52 enhances nuclear translocation and activation of AR by interacting with its NH(2)-terminal domain and enhances the recruitment of coactivators such as p300 to the promoters of AR-dependent genes. These results were confirmed in three different prostate cancer cell lines: LAPC-4 (wild-type AR), LNCaP (mutant AR), and C4-2 (castration resistant). Transfection of p52 into LAPC-4 and LNCaP cells (which express low levels of p52) showed increased activation of the endogenous AR. Downregulation of endogenous p52 in C4-2 cells resulted in abrogation of AR constitutive activation. Comparison of the relative effects of p52 and p65 (RelA) showed that p52, but not p65, could activate the AR. Collectively, these findings, together with previous reports that the levels of NF-kappaB2/p52 are elevated in prostate cancer cells and that active NF-kappaB2/p52 promotes prostate cancer cell growth in vitro and in vivo, suggest that NF-kappaB2/p52 may play a critical role in the progression of castration-resistant prostate cancer.

  17. Androgen regulation of aldehyde dehydrogenase 1A3 (ALDH1A3) in androgen responsive human prostate cancer cell LNCaP.

    Science.gov (United States)

    Previous gene array data from our laboratory identified the retinoic acid (RA) biosynthesis enzyme aldehyde dehydrogenase 1A3 (ALDH1A3) as a putative androgen-responsive gene in prostate cancer epithelial cells (LNCaP). In the present study we attempted to identify if any of the three ALDH1A/RA synt...

  18. Androgen-Sensitized Apoptosis of HPr-1AR Human Prostate Epithelial Cells.

    Directory of Open Access Journals (Sweden)

    Congcong Chen

    Full Text Available Androgen receptor (AR signaling is crucial to the development and homeostasis of the prostate gland, and its dysregulation mediates common prostate pathologies. The mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells have been investigated in human and rodent adult prostate. However, the cellular stress response of human prostate epithelial cells is not well understood, though it is central to prostate health and pathology. Here, we report that androgen sensitizes HPr-1AR and RWPE-AR human prostate epithelial cells to cell stress agents and apoptotic cell death. Although 5α-dihydrotestosterone (DHT treatment alone did not induce cell death, co-treatment of HPr-1AR cells with DHT and an apoptosis inducer, such as staurosporine (STS, TNFt, or hydrogen peroxide, synergistically increased cell death in comparison to treatment with each apoptosis inducer by itself. We found that the synergy between DHT and apoptosis inducer led to activation of the intrinsic/mitochondrial apoptotic pathway, which is supported by robust cleavage activation of caspase-9 and caspase-3. Further, the dramatic depolarization of the mitochondrial membrane potential that we observed upon co-treatment with DHT and STS is consistent with increased mitochondrial outer membrane permeabilization (MOMP in the pro-apoptotic mechanism. Interestingly, the synergy between DHT and apoptosis inducer was abolished by AR antagonists and inhibitors of transcription and protein synthesis, suggesting that AR mediates pro-apoptotic synergy through transcriptional regulation of MOMP genes. Expression analysis revealed that pro-apoptotic genes (BCL2L11/BIM and AIFM2 were DHT-induced, whereas pro-survival genes (BCL2L1/BCL-XL and MCL1 were DHT-repressed. Hence, we propose that the net effect of these AR-mediated expression changes shifts the balance of BCL2-family proteins

  19. Krüppel-like factor 8 is a novel androgen receptor co-activator in human prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hong-jiang HE; Xue-feng GU; Wan-hai XU; De-jun YANG; Xiao-min WANG; Yu SU

    2013-01-01

    Aim: Krüppel-like factor 8 (KLF8) plays important roles in cell cycle and oncogenic transformation.On other hand,androgen receptor (AR) is crucial in development of both androgen-dependent and independent prostatic malignancies.The aim of this study is to investigate the role of KLF8 in prostate cancer (PCa) and the relationship between KLF8 and AR.Methods.: Eight human PCa cell lines,including androgen-dependent LNCap cells and androgen-independent 22Rv1 cells,as well as human PCa samples were studied.LNCap cells and 22Rv1 cells were transfected with plasmids encoding full-length wild-type KLF8 or KLF8 shRNA.The expression of KLF8 protein was detected using Western blotting or immunohistochemical staining.Cell proliferation in vitro was measured with MTT assay,and in vivo in a xenograft nude mouse model.Yeast two-hybrid screening,co-immunoprecipitation and pull down assays were used to examine the binding of KLF8 to AR.Luciferase reporter gene assay was used to measure the transcriptional activity of the genes targeted by AR.Results: In 133 human PCa samples,KLF8 protein staining was observed in 92.65% (63/68) of high-grade PCa,66.15% (43/65) of low-grade PCa,and 6.82% (3/44) of adjacent normal tissues.The expression of KLF8 was significantly associated with poorer overall survival.Overexpression of KLF8 enhanced the proliferation of both LNCap and 22Rv1 cells,while knockdown of endogenous KLF8 suppressed the proliferation.These manipulations exerted similar effects on the tumor volumes in the xenograft nude mouse model.Yeast two-hybrid screening revealed that KLF8 was a novel AR-interacting protein.With pull down assay and co-immunoprecipitation assay,we demonstrated that KLF8 bound directly to AR,and KLF8 enhanced AR target gene transcription.Conclusion: The results demonstrate that KLF8 is a novel AR transcriptional co-activator that is overexpressed in PCa and may play a role in progression of hormone-refractory PCa.

  20. Androgenic suppression combined with radiotherapy for the treatment of prostate adenocarcinoma: a systematic review

    International Nuclear Information System (INIS)

    Locally advanced prostate cancer is often associated with elevated recurrence rates. Despite the modest response observed, external-beam radiotherapy has been the preferred treatment for this condition. More recent evidence from randomised trials has demonstrated clinical benefit with the combined use of androgen suppression in such cases. The aim of this meta-analysis is to compare the combination of distinct hormone therapy modalities versus radiotherapy alone for overall survival, disease-free survival and toxicity. Databases (MEDLINE, EMBASE, LILACS, Cochrane databases and ClinicalTrials.gov) were scanned for randomised clinical trials involving radiotherapy with or without androgen suppression in local prostate cancer. The search strategy included articles published until October 2011. The studies were examined and the data of interest were plotted for meta-analysis. Survival outcomes were reported as a hazard ratio with corresponding 95% confidence intervals. Data from ten trials published from 1988 to 2011 were included, comprising 6555 patients. There was a statistically significant advantage to the use of androgen suppression, in terms of both overall survival and disease free survival, when compared to radiotherapy alone. The use of long-term goserelin (up to three years) was the strategy providing the higher magnitude of clinical benefit. In contrast to goserelin, there were no trials evaluating the use of other luteinizing hormone-releasing hormone (LHRH) analogues as monotherapy. Complete hormonal blockade was not shown to be superior to goserelin monotherapy. Based on the findings of this systematic review, the evidence supports the use of androgen suppression with goserelin monotherapy as the standard treatment for patients with prostate cancer treated with radiotherapy, which are at high risk of recurrence or metastases

  1. Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Michelle A Schultz

    Full Text Available Despite androgen deprivation therapy (ADT, persistent androgen receptor (AR signaling enables outgrowth of castration resistant prostate cancer (CRPC. In prostate cancer (PCa cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone-mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP and castration resistant (C4-2B PCa cells. Dihydrotestosterone (DHT stimulated transactivation of the androgen response element (ARE was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4-2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells.

  2. Human heterochromatin protein 1 isoforms regulate androgen receptor signaling in prostate cancer.

    Science.gov (United States)

    Itsumi, Momoe; Shiota, Masaki; Yokomizo, Akira; Kashiwagi, Eiji; Takeuchi, Ario; Tatsugami, Katsunori; Inokuchi, Junichi; Song, Yoohyun; Uchiumi, Takeshi; Naito, Seiji

    2013-06-01

    Androgen receptor (AR) signaling is critical for the tumorigenesis and development of prostate cancer, as well as the progression to castration-resistant prostate cancer. We previously showed that the heterochromatin protein 1 (HP1) β isoform plays a critical role in transactivation of AR signaling as an AR coactivator that promotes prostate cancer cell proliferation. However, the roles of other HP1 isoforms, HP1α and HP1γ, in AR expression and prostate cancer remain unclear. Here, we found that knockdown of HP1γ, but not HP1α, reduced AR expression and cell proliferation by inducing cell cycle arrest at G1 phase in LNCaP cells. Conversely, overexpression of full-length HP1α and its C-terminal deletion mutant increased AR expression and cell growth, whereas overexpression of HP1γ had no effect. Similarly, HP1α overexpression promoted 22Rv1 cell growth, whereas HP1γ knockdown reduced the proliferation of CxR cells, a castration-resistant LNCaP derivative. Taken together, HP1 isoforms distinctly augment AR signaling and cell growth in prostate cancer. Therefore, silencing of HP1β and HP1γ may be a promising therapeutic strategy for treatment of prostate cancer.

  3. HDAC6 regulates androgen receptor hypersensitivity and nuclear localization via modulating Hsp90 acetylation in castration-resistant prostate cancer.

    Science.gov (United States)

    Ai, Junkui; Wang, Yujuan; Dar, Javid A; Liu, June; Liu, Lingqi; Nelson, Joel B; Wang, Zhou

    2009-12-01

    The development of castration-resistant prostate cancer (PCa) requires that under castration conditions, the androgen receptor (AR) remains active and thus nuclear. Heat shock protein 90 (Hsp90) plays a key role in androgen-induced and -independent nuclear localization and activation of AR. Histone deacetylase 6 (HDAC6) is implicated, but has not been proven, in regulating AR activity via modulating Hsp90 acetylation. Here, we report that knockdown of HDAC6 in C4-2 cells using short hairpin RNA impaired ligand-independent nuclear localization of endogenous AR and inhibited PSA expression and cell growth in the absence or presence of dihydrotestosterone (DHT). The dose-response curve of DHT-stimulated C4-2 colony formation was shifted by shHDAC6 such that approximately 10-fold higher concentration of DHT is required, indicating a requirement for HDAC6 in AR hypersensitivity. HDAC6 knockdown also inhibited C4-2 xenograft tumor establishment in castrated, but not in testes-intact, nude mice. Studies using HDAC6-deficient mouse embryonic fibroblasts cells showed that inhibition of AR nuclear localization by HDAC6 knockdown can be largely alleviated by expressing a deacetylation mimic Hsp90 mutant. Taken together, our studies suggest that HDAC6 regulates AR hypersensitivity and nuclear localization, mainly via modulating HSP90 acetylation. Targeting HDAC6 alone or in combination with other therapeutic approaches is a promising new strategy for prevention and/or treatment of castration-resistant PCa.

  4. An update of RTOG clinical trials of combined androgen suppression and radiation in localized prostatic carcinoma

    International Nuclear Information System (INIS)

    Over the last ten years the RTOG has evaluated, by 5 Phase III trials, (two are ongoing and three have been completed) the potential clinical gains of neoadjuvant Maximal Androgen Blockade (MAB), Zoladex monthly and Flutamide daily, of adjuvant LHRH agonists (Zoladex) therapy and of the sequencing of four months of MAB with radiation (neoadjuvant vs. adjuvant). Two additional Phase III trails for men with locally advanced prostate cancer are soon to open. One will evaluate the potential gains in survival of salvage radiation therapy plus adjuvant anti-androgen therapy, compared to salvage radiation alone, for patients with an elevated PSA following radical prostatectomy for pathologic state T3, NO tumors; and a second Phase III trial to evaluate the potential gain of external beam irradiation added to life-long MAB for patients with pathologically proven metastases to the pelvic lymph nodes from prostatic carcinoma. The endpoints of this trial will be overall and disease-specific survival as well as life long symptomatic local control and other quality of life issues. During our next grant period we anticipate that our accrual of over 2500 patients to randomized trials for patients with prostate cancer will be increased by 20-30% with the addition of many RTOG associate and affiliated members along with the CCOP institutions. the identification of significant increases in freedom from any progression and freedom from distant metastases by androgen suppression of limited duration have been reported already in two of our trials (RTOG 86-10 and RTOG 85-31) although no clear overall survival benefits are yet demonstrated. Nevertheless these impressive results have had a major impact nationally on the treatment of patients with locally advanced prostatic cancer

  5. Changes in gene expression following androgen receptor blockade is not equivalent to androgen ablation by castration in the rat ventral prostate

    Indian Academy of Sciences (India)

    Anil M Limaye; Irfan Asangani; Thyagarajan Kalyani; Paturu Kondaiah

    2008-06-01

    Involution of the rat ventral prostate and concomitant modulation of gene expression post-castration is a well-documented phenomenon. While the rat castration model has been extensively used to study androgen regulation of gene expression in the ventral prostate, it is not clear whether all the gene expression changes post-castration are due to androgen depletion alone. To obtain insights into this, we performed differential display reverse transcriptase polymerase chain reaction (DD-RT-PCR) which resulted in the identification of castration and/or flutamide-regulated genes in the rat ventral prostate. These include clusterin, methionine adenosyl transferase II, and prostate-specific transcripts such as PBPC1BS, S100RVP and A7. While clusterin, PBPC1BS and methionine adenosyl transferase II are regulated by both castration and flutamide, S100 RVP and A7 are regulated by castration alone. Interestingly, we show that flutamide, unlike castration, does not induce apoptosis in the rat ventral prostate epithelium, which could be an underlying cause for the differential effects of castration and flutamide treatment. We propose that castration leads to enrichment and depletion of stromal and epithelial cell types, respectively, resulting in erroneous conclusions on some of the cell type-specific transcripts as being androgen regulated.

  6. Androgen Deprivation Therapy and the Incidence of Inflammatory Bowel Disease in Patients With Prostate Cancer.

    Science.gov (United States)

    Klil-Drori, Adi J; Tascilar, Koray; Yin, Hui; Aprikian, Armen; Bitton, Alain; Azoulay, Laurent

    2016-07-01

    Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. By lowering androgen levels, ADT inhibits the progression of prostate cancer, but it may also affect gut autoimmunity. We investigated the association between ADT and the incidence of inflammatory bowel disease using a cohort of 31,842 men newly diagnosed with prostate cancer between 1988 and 2014, identified in the United Kingdom Clinical Practice Research Datalink. Exposure to ADT was treated as a time-varying variable and lagged by 1 year to account for diagnostic delays, with nonuse as the reference category. During 133,018 person-years of follow-up, 48 men were newly diagnosed with ulcerative colitis (incidence rate (IR) = 36/100,000 person-years (PY)) and 12 were diagnosed with Crohn's disease (IR = 9/100,000 PY). In Cox proportional hazards models, ADT was associated with a decreased risk of ulcerative colitis (IR = 24/100,000 PY vs. IR = 50/100,000 PY; hazard ratio = 0.52, 95% confidence interval: 0.28, 0.99) and a nonsignificant decreased risk of Crohn's disease (hazard ratio = 0.38, 95% confidence interval: 0.11, 1.37). These findings indicate that the use of ADT may be associated with intestinal autoimmunity. Further research is warranted to replicate these findings and assess their clinical significance. PMID:27268031

  7. Androgen receptor CAG polymorphism and the risk of benign prostatic hyperplasia in a Brazilian population

    Directory of Open Access Journals (Sweden)

    Vanderlei Biolchi

    2012-06-01

    Full Text Available Benign prostatic hyperplasia (BPH is a very frequent age-related proliferative abnormality in men. Polymorphic CAG repeat in the androgen receptor (AR can alter transactivation of androgen-responsive genes and potentially influence BPH risk. We investigated the association between CAG repeat length and risk of BPH in a case-control study of a Brazilian population. We evaluated 214 patients; 126 with BPH and 88 healthy controls. DNA was extracted from peripheral leucocytes and the AR gene was analyzed using fragment analysis. Hazard ratio (HR and 95% confidence interval were estimated using logistic regression models. Mean CAG length was not different between patients with BPH and controls. The CAG repeat length was examined as a categorical variable (CAG 21 and CAG 22 and did not differ between the control vs. the BPH group. We found no evidence for an association between AR CAG repeat length in BPH risk in a population-based sample of Brazilians.

  8. Androgens.

    Science.gov (United States)

    Iyer, Rakesh; Handelsman, David J

    2016-01-01

    Androgen abuse is the most potent and prevalent form of sports doping detected. It originated from the early years of the Cold War as an epidemic confined to drug cheating within elite power sports. In the decades following the end of the Cold War, it has become disseminated into an endemic based within the illicit drug subcultures serving recreational abusers seeking cosmetic body sculpting effects. Within sports, both direct androgen abuse (administration of androgens), as well as indirect androgen abuse (administration of nonandrogenic drugs to increase endogenous testosterone), is mostly readily detectable with mass spectrometry-based anti-doping urine tests. The ongoing temptation of fame and fortune and the effectiveness of androgen abuse in power sports continue to entice cheating via renewed approaches aiming to exploit androgens. These require ongoing vigilance, inventiveness in anti-doping science, and targeting coaches as well as athletes in order to build resilience against doping and maintain fairness in elite sport. The challenge of androgen abuse in the community among recreational abusers has barely been recognized and effective approaches remain to be developed. PMID:27347677

  9. Integrating diet and exercise into care of prostate cancer patients on androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Moyad MA

    2016-08-01

    Full Text Available Mark A Moyad,1 Robert U Newton,2 Ulf W Tunn,3 Damian Gruca4 1Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA; 2Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia; 3Urological Clinic, Facharztzentrum Academic Hospital Sana Klinikum Offenbach, Offenbach/Main, 4Global Medical Affairs, AbbVie Deutschland, Ludwigshafen, Germany Abstract: Improved diagnosis and treatment regimens have resulted in greater longevity for men with prostate cancer. This has led to an increase in both androgen deprivation therapy (ADT use and duration of exposure, and therefore to its associated adverse effects, such as sexual dysfunction, osteoporosis, reduced muscle mass, increased fat mass, and increased incidence of cardiovascular disease and type 2 diabetes. Given that the adverse effects of ADT are systemic, often debilitating, and difficult to treat, efforts continue in the development of new strategies for long-term management of prostate cancer. The PubMed database was searched to select trials, reviews, and meta-analyses in English using such search terms as “prostate cancer” and “androgen deprivation therapy”, “cardiovascular risk”, “lean body mass”, “exercise”, and “diet”. The initial searches produced 379 articles with dates 2005 or more recent. Articles published after 2004 were favored. This review utilizes the latest data to provide a status update on the effects of exercise and diet on patients with prostate cancer, focusing on ADT-associated side effects, and it discusses the evidence for such interventions. Since the evidence of large-scale trials in patients with prostate cancer is missing, and an extrapolation of supporting data to all patient subgroups cannot be provided, individualized risk assessments remain necessary before the initiation of exercise and diet programs. Exercise, diet, and nutritional supplementation interventions have the potential to

  10. The Nrf1 and Nrf2 Balance in Oxidative Stress Regulation and Androgen Signaling in Prostate Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Schultz, Michelle A. [Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States); Abdel-Mageed, Asim B. [Department of Urology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States); Mondal, Debasis, E-mail: dmondal@tulane.edu [Department of Pharmacology, Tulane University Medical Center, 1430 Tulane Avenue, New Orleans, LA 70112 (United States)

    2010-06-21

    Reactive oxygen species (ROS) signaling has recently sparked a surge of interest as being the molecular underpinning for cancer cell survival, but the precise mechanisms involved have not been completely elucidated. This review covers the possible roles of two ROS-induced transcription factors, Nrf1 and Nrf2, and the antioxidant proteins peroxiredoxin-1 (Prx-1) and Thioredoxin-1 (Txn-1) in modulating AR expression and signaling in aggressive prostate cancer (PCa) cells. In androgen independent (AI) C4-2B cells, in comparison to the parental androgen dependent (AD) LNCaP cells, we present evidence of high Nrf1 and Prx-1 expression and low Nrf2 expression in these aggressive PCa cells. Furthermore, in DHT treated C4-2B cells, increased expression of the p65 (active) isoform of Nrf1 correlated with enhanced AR transactivation. Our findings implicate a crucial balance of Nrf1 and Nrf2 signaling in regulating AR activity in AI-PCa cells. Here we will discuss how understanding the mechanisms by which oxidative stress may affect AR signaling may aid in developing novel therapies for AI-PCa.

  11. The Adipocyte-Derived Hormone Leptin Has Proliferative Actions on Androgen-Resistant Prostate Cancer Cells Linking Obesity to Advanced Stages of Prostate Cancer

    Directory of Open Access Journals (Sweden)

    M. Raschid Hoda

    2012-01-01

    Full Text Available Background. Because obesity may be a risk factor for prostate cancer, we investigated proliferative effects of adipocytes-derived hormone leptin on human prostate cancer cells and assessed the role of mitogen-activated protein kinase (MAPK signaling pathway in mediating these actions. Material and Methods. Three human prostate cancer cell lines were treated with increasing doses of recombinant leptin. Cell growth was measured under serum-free conditions using a spectrophotometric assay. Further, Western blotting was applied to detect the phosphorylation of an ERK1/2, and a specific inhibitor of MAPK (PD98059; 40 μM was used. Results. In both androgen-resistant cell lines DU145 and PC-3, cell growth was dose-dependently increased by leptin after 24 hrs and 48 hrs of incubation, whereas leptin’s proliferative effects on androgen-sensitive cell line LNCaP was less pronounced. Further, leptin caused dose-dependent ERK1/2 phosphorylation in both androgen-resistant cell lines, and pretreatment of these cells with PD98059 inhibited these responses. Conclusions. Leptin may be a potential link between obesity and risk of progression of prostate cancer. Thus, studies on leptin and obesity association to prostate cancer should differentiate patients according to androgen sensitivity.

  12. Molecular insight into the differential anti-androgenic activity of resveratrol and its natural analogs: In Silico approach to understand biological actions

    Science.gov (United States)

    The androgen receptor (AR) is a therapeutic target for the treatment of prostate cancer. Androgen receptor reactivation during the androgen-independent stage of prostate cancer is mediated by numerous mechanisms including expression of AR mutants and splice variants that become non-responsive to con...

  13. Bone mineral density in Jamaican men on androgen deprivation therapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    Mayhew Richard G

    2011-09-01

    Full Text Available Abstract Background Androgen deprivation therapy (ADT has been reported to reduce the bone mineral density (BMD in men with prostate cancer (CaP. However, Afro-Caribbeans are under-represented in most studies. The aim was to determine the effect of androgen deprivation therapy (ADT on the bone mineral density (BMD of men with prostate cancer in Jamaica. Methods The study consisted of 346 Jamaican men, over 40 years of age: 133 ADT treated CaP cases (group 1, 43 hormone-naïve CaP controls (group 2 and 170 hormone naïve controls without CaP (group 3. Exclusion criteria included metastatic disease, bisphosphonate therapy or metabolic disease affecting BMD. BMD was measured with a calcaneal ultrasound and expressed in S.D. units relative to young adult men (T score, according to the World Health Organization definition. Patient weight, height and BMI were assessed. Results Mean ± sd, age of patients in group 1 (75± 7.4 yrs was significantly greater than groups 2 and 3 (67 ± 8.1 yrs; 65±12.0 yrs. There was no significant difference in weight and BMI between the 3 groups. . The types of ADT (% of cases, median duration in months with IQR included LHRH (Luteinizing hormone releasing hormone analogues (28.6%, 17.9, IQR 20.4, oestrogens (9.8%, 60.5, IQR 45.6 anti-androgens (11.3%, 3.3, IQR 15.2 and orchiectomy (15.7%, 43.4, IQR 63.9. Unadjusted t score of group 1, mean ± sd, (-1.6± 1.5 was significantly less than group 2 (-0.9±1.1 and group 3 (-0.7±1.4, p Conclusions ADT is associated with lower BMD in Jamaican men on hormonal therapy for prostate cancer.

  14. Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway.

    Science.gov (United States)

    Ardiani, Andressa; Gameiro, Sofia R; Kwilas, Anna R; Donahue, Renee N; Hodge, James W

    2014-10-15

    Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone render prostate tumor cells more sensitive to T cell-mediated lysis through immunogenic modulation, and that these immunomodulatory activities are androgen receptor (AR)-dependent. In studies reported here, the NAIP gene was significantly down-regulated in human prostate tumor cells treated in vitro and in vivo with enzalutamide. Functional analysis revealed that NAIP played a critical role in inducing CTL sensitivity. Amplification of AR is a major mechanism of resistance to androgen-deprivation therapy (ADT). Here, we show that enzalutamide enhances sensitivity to immune-mediated killing of prostate tumor cells that overexpress AR. The immunomodulatory properties of enzalutamide and abiraterone provide a rationale for their use in combination with immunotherapeutic agents in CRPC, especially for patients with minimal response to enzalutamide or abiraterone alone, or for patients who have developed resistance to ADT. PMID:25344864

  15. Possible mechanism of benign prostatic hyperplasia induced by androgen-estrogen ratios in castrated rats

    Directory of Open Access Journals (Sweden)

    Xiang-Yun Liu

    2010-01-01

    Full Text Available Objectives : To explore the role of androgen-estrogen balance in benign prostatic hyperplasia (BPH induced by varying doses of estradiol/testosterone propionate (E 2 /TP in castrated rats. Materials and Methods : A total of 222 rats were divided into 37 groups at random, including 35 groups of different E 2 /TP, one control, and one castrated group. All 37 groups except the control group were castrated, for eliminating endogenesis of testosterone in rats. The treated groups were administered testosterone propionate (TP; at the dosages of 0.15, 0.74, 3.7, 18.5, and 92.6 mg/kg, combined with estradiol (E 2 ; at the dosage of 0, 0.4, 2, 10, 50, 250, and 1250 μg/kg diluted in vegetable oil for 30 days, respectively, whereas the control groups received only vegetable oil. All prostate specimens were removed under anesthesia, then fixed and embedded in paraffin, for measuring the organ quotient, volume, area of prostate glandular cavity, and the height of prostate epithelia. Results : When the dosages of TP were 0.15, 3.7, 18.5, and 92.6 mg/kg, the degree of prostatic hyperplasia had no obvious dose-effect relationship with E 2 . When TP was 0.74 mg/kg, with the increase of the dosage of E 2 , the volume and quotient of prostate were increasing. However, when the dosage of E 2 exceeded 50 μg/kg, E 2 /TP was 5/74, the prostatic volume did not increase obviously. Conclusion : The proper levels of E2/TP play an important role in the pathogenesis of BPH. In rats, the balance point of E 2 /TP is 5/74.

  16. The Androgen Receptor Regulates PPARγ Expression and Activity in Human Prostate Cancer Cells.

    Science.gov (United States)

    Olokpa, Emuejevoke; Bolden, Adrienne; Stewart, LaMonica V

    2016-12-01

    The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPARγ within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPARγ expression and function within human prostate cancer cells. qRT-PCR and Western blot analyses revealed nanomolar concentrations of the AR agonist dihydrotestosterone (DHT) decrease PPARγ mRNA and protein within the castration-resistant, AR-positive C4-2 and VCaP human prostate cancer cell lines. The AR antagonists bicalutamide and enzalutamide blocked the ability of DHT to reduce PPARγ levels. In addition, siRNA mediated knockdown of AR increased PPARγ protein levels and ligand-induced PPARγ transcriptional activity within the C4-2 cell line. Furthermore, proteasome inhibitors that interfere with AR function increased the level of basal PPARγ and prevented the DHT-mediated suppression of PPARγ. These data suggest that AR normally functions to suppress PPARγ expression within AR-positive prostate cancer cells. To determine whether increases in AR protein would influence PPARγ expression and activity, we used lipofectamine-based transfections to overexpress AR within the AR-null PC-3 cells. The addition of AR to PC-3 cells did not significantly alter PPARγ protein levels. However, the ability of the PPARγ ligand rosiglitazone to induce activation of a PPARγ-driven luciferase reporter and induce expression of FABP4 was suppressed in AR-positive PC-3 cells. Together, these data indicate AR serves as a key modulator of PPARγ expression and function within prostate tumors. J. Cell. Physiol. 231: 2664-2672, 2016. © 2016 Wiley Periodicals, Inc. PMID:26945682

  17. A novel selective androgen receptor modulator, NEP28, is efficacious in muscle and brain without serious side effects on prostate.

    Science.gov (United States)

    Akita, Kazumasa; Harada, Koichiro; Ichihara, Junji; Takata, Naoko; Takahashi, Yasuhiko; Saito, Koichi

    2013-11-15

    Age-related androgen depletion is known to be a risk factor for various diseases, such as osteoporosis and sarcopenia. Furthermore, recent studies have demonstrated that age-related androgen depletion results in accumulation of β-amyloid protein and thereby acts as a risk factor for the development of Alzheimer's disease. Supplemental androgen therapy has been shown to be efficacious in treating osteoporosis and sarcopenia. In addition, studies in animals have demonstrated that androgens can play a protective role against Alzheimer's disease. However, androgen therapy is not used routinely for these indications, because of side effects. Selective androgen receptor modulators (SARMs) are a new class of compounds. SARMs maintain the beneficial effects of androgens on bone and muscle while reducing unwanted side effects. NEP28 is a new SARM exhibiting high selectivity for androgen receptor. To investigate the pharmacological effects of NEP28, we compared the effects on muscle, prostate, and brain with mice that were androgen depleted by orchidectomy and then treated with either placebo, NEP28, dihydrotestosterone, or methyltestosterone. We demonstrated that NEP28 showed tissue-selective effect equivalent to or higher than existing SARMs. In addition, the administration of NEP28 increased the activity of neprilysin, a known Aβ-degrading enzyme. These results indicate that SARM is efficacious for the treatment of not only osteoporosis and sarcopenia, but also Alzheimer's disease.

  18. Emerging potential of parenteral estrogen as androgen deprivation therapy for prostate cancer

    Directory of Open Access Journals (Sweden)

    Syed Imran Ali Shah

    2015-01-01

    Full Text Available Androgen deprivation therapy (ADT is a key management strategy for prostate cancer (PC, achieved commonly by administration of luteinizing hormone-releasing hormone agonist (LHRHa, ADT markedly suppresses both male and female sex hormones which results in "castration syndrome", a constellation of adverse events such as muscle weakness, impairment of glucose and lipid metabolism, impotence, osteoporosis, and fractures. Recent evidence suggests that estrogen, in the parenteral form, may emerge as an alternative to LHRHa as it offers potential benefits of arresting PC growth as well as avoiding some of the estrogen deficiency related toxicities of LHRHa by maintaining endogenous levels of estrogen.

  19. Maximum vs. Mono Androgen Blockade and the Risk of Recurrence in Men With Localized Prostate Cancer Undergoing Brachytherapy

    International Nuclear Information System (INIS)

    Purpose: We examined whether maximum androgen blockade (MAB) is associated with a decreased recurrence risk vs. single-agent androgen suppression (monotherapy) for men undergoing brachytherapy (BT) for localized prostate cancer. Methods and Materials: Data from 223 men in Cancer of the Prostate Strategic Urologic Research Endeavor database who received androgen deprivation therapy (ADT) concurrent with BT for intermediate- or high-risk prostatic adenocarcinoma were included; 159 (71%) received MAB, and 64 (29%) monotherapy (luteinizing hormone-releasing hormone agonist or anti-androgen alone). Cox regression analysis was performed to assess whether the choice of ADT was associated with disease recurrence adjusting for known prognostic factors. Results: Men who received MAB had similar Gleason scores, T categories, and pretreatment prostate-specific antigen as those who received monotherapy. After a median follow-up of 49 months, the use of MAB was not associated with a decrease in the risk recurrence (p = 0.72), after adjusting for known prognostic factors. A higher PSA at diagnosis (p = 0.03) and younger age at diagnosis (p < 0.01) were associated with increased recurrence risk. The 3-year recurrence free survival was 76% for patients in both monotherapy and MAB groups. Conclusions: There are varied practice patterns in physicians' choice of the extent of concurrent ADT when used with brachytherapy for men with intermediate- or high-risk prostate cancer. Given a lack of demonstrated superiority from either ADT choice, both appear to be reasonable options.

  20. Genipin blocks Uncoupling protein 2 in the inhibition effect of energy production and growth on androgen independent prostate cancer cells%京尼平阻断线粒体解耦联蛋白2对激素非依赖性前列腺癌细胞产能及生长的抑制作用

    Institute of Scientific and Technical Information of China (English)

    杨清滔; 谷江; 张永春; 朱致晖; 杨永安; 王楠; 祝庆亮; 姚茂良

    2014-01-01

    目的 从能量生成角度研究京尼平(Genipin)对激素非依赖性前列腺癌(AIPC)的抑制作用是否与线粒体解耦联蛋白2(UCP2)被阻断有关,并探讨其临床意义.方法 以低、中、高(40、80、120 μmol/L)剂量Genipin干预PC-3细胞培养基48 h,噻唑蓝(MTT)和流式细胞仪检测细胞增殖及凋亡,实时荧光定量聚合酶链反应(Real-time PCR)、Western blot检测UCP2表达,荧光探针检测细胞内Ca2含量,分光光度计检测线粒体膜电势(△ψm)、膜通透性转换孔(mPTP)变化及三磷酸腺苷(ATP)含量.结果 Genipin能显著抑制PC-3细胞增殖,其中对照组及低、中、高剂量组细胞凋亡率分别为(7.60±1.48)%、(9.38±1.01)%、(20.77±1.14)%、(23.48±1.99)%,Genipin可降低UCP2表达,此时细胞内Ca2含量明显增加,且mPTP开放程度增加及△ψm减小,ATP生成明显减少,其中对照组及低、中、高剂量组ATP含量分别为(0.120 ±0.015)、(0.110 ±0.013)、(0.080 ±0.007)、(0.050 ±0.008) mmol/L,以上改变均与Genipin浓度呈正相关,且各组间比较差异均有统计学意义(P<0.05).结论 Genipin能明显抑制AIPC细胞的增殖,该抑制作用可能与其阻断UCP2,导致线粒体功能异常,ATP生成减少有关.%Objective To investigate whether uncoupling protein 2 (UCP2) blocked was participated in genipin inhibiting proliferation of androgen independent prostate cancer cells from the perspective of energy,and to explore its clinical significance.Methods PC-3 cells were cultured in vitro,three concentrations of genipin solutions were added to the culture medium.The differences in proliferation,apoptosis,expressions of UCP2,levels of Ca2+,mitochondrion membrane potential (△ψm),membrane permeability transition pore (mPTP) and adenosine triphosphate (ATP) between before and after treated with various concentrations of genipin were measured by methyl thiazolyl tetrazolium (MTT) assay,flow cytometry assay,Real-time polymerase chain reaction

  1. Estrogen receptors α and β and aromatase as independent predictors for prostate cancer outcome

    Science.gov (United States)

    Grindstad, Thea; Skjefstad, Kaja; Andersen, Sigve; Ness, Nora; Nordby, Yngve; Al-Saad, Samer; Fismen, Silje; Donnem, Tom; Khanehkenari, Mehrdad Rakaee; Busund, Lill-Tove; Bremnes, Roy M.; Richardsen, Elin

    2016-01-01

    Androgens are considered important in normal prostate physiology and prostate cancer (PCa) pathogenesis. However, androgen-targeted treatment preventing PCa recurrence is still lacking. This indicates additional mediators contributing to cancer development. We sought to determine the prognostic significance of estrogen receptors, ERα and -β, and the aromatase enzyme in PCa. Tissue microarrays were created from 535 PCa patients treated with radical prostatectomy. Expression of ERα, ERβ and aromatase were evaluated using immunohistochemistry. Representative tumor epithelial (TE) and tumor stromal (TS) areas were investigated separately. Survival analyses were used to evaluate the markers correlation to PCa outcome. In univariate analyses, ERα in TS was associated with delayed time to clinical failure (CF) (p = 0.042) and PCa death (p = 0.019), while ERβ was associated with reduced time to biochemical failure (BF) (p = 0.002). Aromatase in TS and TE was associated with increased time to BF and CF respectively (p = 0.016, p = 0.046). Multivariate analyses supported these observations, indicating an independent prognostic impact of all markers. When stratifying the analysis according to different surgical centers the results were unchanged. In conclusion, significant prognostic roles of ERα, ERβ and aromatase were discovered in the in PCa specimens of our large multicenter cohort. PMID:27610593

  2. Asian trends in primar y androgen depletion therapy on prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Hideyuki Akaza

    2013-01-01

    hTere are notable differences in the incidence and mortality rates for prostate cancer between Asia and Western countries. It is also recognized that there are differences in thinking with regard to treatment options. Recently it is also the case that opinions have been reported concerning the differences between Asian and Western patients with regard to their reaction to androgen depletion therapy (ADT). Given that ADT is a method of treatment that focuses on the elimination of testosterone, an inevitable symptom of its administration is testosterone losing syndrome. It is for this reason that in Western countries ADT has only been recommended in cases of advanced or metastatic cancer. On the other hand, in Asia, ADT is used in relatively many cases, including non-metastatic localized cancer and invasive localized cancer. To date, however, there has been little substantive discussion concerning this difference in utilization of ADT. ADT-related drugs for prostate cancer and the development of new drugs for castration resistant prostate cancer (CRPC) have been actively tested in recent years. It could be the case that analyzing the differences in concepts about ADT between Asia and the West could contribute to the effective use of ADT-related drugs and also help to build new treatment strategies for prostate cancer.

  3. The lived experience of physically active older prostate cancer survivors on androgen deprivation therapy.

    Science.gov (United States)

    Wright-St Clair, Valerie A; Malcolm, Wanda; Keogh, Justin W L

    2014-03-01

    This study sought to explore the lived experiences of physically active prostate cancer survivors on androgen deprivation therapy (ADT), who exercise individually. Three older men (74-88 years old) with prostate cancer, using ADT continuously for at least 12 months and regularly exercising for at least 6 months, participated in this qualitative pilot study, informed by interpretive phenomenology. Data were gathered using individual semi-structured interviews, audio recorded and transcribed verbatim. Coherent stories were drawn from each transcript and analyzed using iterative and interpretive methods. van Manen's lifeworld existentials provided a framework for interpreting across the research text. Three notions emerged: Getting started, Having a routine and Being with music. Together they reveal what drew the participants to exercising regularly despite the challenges associated with their cancer and treatments. This study provides insights into the benefits of, and what it means for, older men with prostate cancer to regularly exercise individually. These findings may assist cancer clinicians and other allied health professionals to be more attuned to prostate cancer survivors' lived experiences when undergoing ADT, allowing clinicians to better promote regular exercise to their patients as a foundational component of living well. PMID:23862577

  4. ERG Cooperates with Androgen Receptor in Regulating Trefoil Factor 3 in Prostate Cancer Disease Progression

    Directory of Open Access Journals (Sweden)

    David S. Rickman

    2010-12-01

    Full Text Available To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC, we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3 emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

  5. ERG cooperates with androgen receptor in regulating trefoil factor 3 in prostate cancer disease progression.

    Science.gov (United States)

    Rickman, David S; Chen, Ying-Bei; Banerjee, Samprit; Pan, Yihang; Yu, Jindan; Vuong, Terry; Perner, Sven; Lafargue, Christopher J; Mertz, Kirsten D; Setlur, Sunita R; Sircar, Kanishka; Chinnaiyan, Arul M; Bismar, Tarek A; Rubin, Mark A; Demichelis, Francesca

    2010-12-01

    To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

  6. Phytoestrogens selective for the estrogen receptor beta exert anti-androgenic effects in castration resistant prostate cancer.

    Science.gov (United States)

    Thelen, Paul; Wuttke, Wolfgang; Seidlová-Wuttke, Dana

    2014-01-01

    Prostate cancer is the leading cause of cancer death in men of the Western world. A castration-resistant prostate cancer (CRPC) eventually will arise when a local restricted prostate carcinoma was not cured duly by radical prostatectomy or radiation therapy. Although androgen ablation therapies are considered the gold standard for treatments of advanced prostate cancer there is no curative therapy available at present. In previous pre-clinical and clinical trials several phytoestrogens were investigated for their anticancer potential in various models for prostate cancer. Phytoestrogens feature tumour preventive characteristics and most probably are involved in the low incidence rate of hormone related cancers in Asian countries. Phytoestrogens such as isoflavones can have a marked impact on the most essential therapy target of CRPC i.e. the androgen receptor. Furthermore, functional analyses solidified the notion of such drugs as androgen antagonistic. Phytoestrogens commonly feature low toxicity combined with a potential of targeted therapy. Thus, these drugs qualify for conceivable implementation in prostate cancer patients under active surveillance. In addition, relapse prevention with these drugs after radical prostatectomy or radiation therapy might be considered. This article is part of a Special Issue entitled 'Phytoestrogens'.

  7. Prognostic significance of genetic polymorphisms in disease progression and survival in prostate cancer after androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Tsung-Yi Huang

    2015-06-01

    Full Text Available It is believed that androgens and their receptors regulate normal prostate growth and mediate prostate cancer development. Androgen deprivation therapy is the most commonly used treatment for advanced prostate cancer. Although the therapy is initially effective, progression of the disease to castration-resistant prostate cancer is almost inevitable, leading to treatment failure. Despite the existence of current clinical parameters, new biomarkers are urgently needed to improve the prognosis. Some molecules and DNA-based genetic biomarkers are under investigation as potential prognostic factors. The advancement in molecular cytogenetic research, such as genome-wide association for single-nucleotide polymorphisms, has made possible the detection of genetic mutations. In this study, a literature search from August 1985 to April 2013 was performed through the PubMed database using the keywords “genetic polymorphisms”, “prostate cancer” and “androgen deprivation therapy”. The results revealed that several genome-wide association studies (such as rs16901979, rs7931342, HSD17B4, rs6162 in the CYP17A1, rs4243229 and rs7201637 in the HSD17B2, rs1062577 in the ESR1, SLCO1B3, SLCO2B1, rs2939244 in the ARRDC3, rs9508016 in the FLT1, rs6504145 in the SKAP1, rs7830611 in the FBXO32, rs9508016 in the FLT1, rs12529 in the AKR1C3, rs16934641 in the BNC2, rs3763763 in the TACC2, rs2051778 in the ALPK1, and rs3763763 in the TACC2, AR, ESR1, and ESR2 and single-nucleotide polymorphisms in important pathways (such as androgen signal, biosynthesis, metabolism, androgen receptor binding site, response element, androgen receptor CAG repeat polymorphism length, and estrogen receptor-binding sites involved in prostate cancer occurrence and mechanism could serve as candidate biomarkers for the early detection of castration-resistant prostate cancer after androgen deprivation therapy. Additional investigations are required to decipher precisely the gene

  8. An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

    Science.gov (United States)

    Imamura, Yusuke; Tien, Amy H.; Pan, Jinhe; Leung, Jacky K.; Banuelos, Carmen A.; Jian, Kunzhong; Wang, Jun; Mawji, Nasrin R.; Fernandez, Javier Garcia; Lin, Kuo-Shyan; Andersen, Raymond J.; Sadar, Marianne D.

    2016-01-01

    Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD–targeted (AR LBD–targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V–positive lesions to determine whether they will benefit from further AR LBD–targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.

  9. Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

    DEFF Research Database (Denmark)

    Hedlund, P.O.; Damber, J.E.; Hagerman, I.;

    2008-01-01

    To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events...

  10. Androgen deprivation therapy sensitizes prostate cancer cells to T-cell killing through androgen receptor dependent modulation of the apoptotic pathway

    OpenAIRE

    Ardiani, Andressa; Gameiro, Sofia R.; Kwilas, Anna R.; Donahue, Renee N.; Hodge, James W.

    2014-01-01

    Despite recent advances in diagnosis and management, prostrate cancer remains the second most common cause of death from cancer in American men, after lung cancer. Failure of chemotherapies and hormone-deprivation therapies is the major cause of death in patients with castration-resistant prostate cancer (CRPC). Currently, the androgen inhibitors enzalutamide and abiraterone are approved for treatment of metastatic CRPC. Here we show for the first time that both enzalutamide and abiraterone r...

  11. A protein in rat prostatic chromatin interacting with androgen regulated gene

    Institute of Scientific and Technical Information of China (English)

    XUYOUHAI; RONGCHANG; 等

    1992-01-01

    2M NaCl-insoluble fraction of rat ventral Prostate chromatin(residual proteins)contain proteins able to interact specifically with androgen-receptor complex and is ,therefore,a part of the aceptor complex.Among residual proteins a 98 KDa protein has been found which binds significantly to a genomic fiagment containing an androgen-regulated gene coding for a 22 KDa protein The biological significance of this binding in androgen action need to be further studied.A mini-plasmid clone containing 22 KDa protein coding sequence was cloned into charon 4A genomic library from which a 5.7 Kb genomic fragment was isolated,identified by hybridization with a 5' and a 3' cDNA probes,and shown to contain the 3' flanking sequence.Restriction enzyme treatment of this fragment yielded a 4.7 Kb restriction fragmwent representing the 5' upstream region and a 1.0 Kb containing part of the coding sequence.Deletion studies indicated that the 97 KDa protein bound only to a subclone of about 300 bp segment .Furthermore,gel shifting experiment supported its DNA-protein binding.

  12. Androgen Induces Adaptation to Oxidative Stress in Prostate Cancer: Implications for Treatment with Radiation Therapy

    Directory of Open Access Journals (Sweden)

    Jehonathan H. Pinthus

    2007-01-01

    Full Text Available Radiation therapy is a standard treatment for prostate cancer (PC. The postulated mechanism of action for radiation therapy is the generation of reactive oxygen species (ROS. Adjuvant androgen deprivation (AD therapy has been shown to confer a survival advantage over radiation alone in high-risk localized PC. However, the mechanism of this interaction is unclear. We hypothesize that androgens modify the radioresponsiveness of PC through the regulation of cellular oxidative homeostasis. Using androgen receptor (AR+ 22rv1 and AR− PC3 human PC cell lines, we demonstrated that testosterone increased basal reactive oxygen species (bROS levels, resulting in dose-dependent activation of phospho-p38 and pAKT, increased expression of clusterin, catalase, manganese superoxide dismutase. Similar data were obtained in three human PC xenografts; WISH-PC14, WISH-PC23, CWR22, growing in testosterone-supplemented or castrated SCID mice. These effects were reversible through AD or through incubation with a reducing agent. Moreover, testosterone increased the activity of catalase, superoxide dismutases, glutathione reductase. Consequently, AD significantly facilitated the response of AR+ cells to oxidative stress challenge. Thus, testosterone induces a preset cellular adaptation to radiation through the generation of elevated bROS, which is modified by AD. These findings provide a rational for combined hormonal and radiation therapy for localized PC.

  13. Establishment of a novel immortalized human prostatic epithelial cell line stably expressing androgen receptor and its application for the functional screening of androgen receptor modulators

    International Nuclear Information System (INIS)

    In this study, we developed a human prostatic epithelial cell line BPH-1-AR stably expressing AR by lentiviral transduction. Characterization by immunoblot and RT-PCR showed that AR was stably expressed in all representative BPH-1-AR clones. Androgen treatment induced a secretory differentiation phenotype in BPH-1-AR cells but suppressed their cell proliferation. Treatments with AR agonists induced transactivation of a transfected PSA-gene promoter reporter in BPH-1-AR cells, whereas this transactivation was suppressed by an AR antagonist flutamide, indicating that the transduced AR in BPH-1-AR cells was functional. Finally, we utilized BPH-1-AR cells to evaluate the androgenic activities and growth effects of five newly developed non-steroidal compounds. Results showed that these compounds showed androgenic activities and growth-inhibitory effects on BPH-1-AR cells. Our results showed that BPH-1-AR cell line would be a valuable in vitro model for the study of androgen-regulated processes in prostatic epithelial cells and identification of compounds with AR-modulating activities.

  14. The effect of 125I labeled anti-androgen receptor agent on the proliferation of prostate cancer cells

    International Nuclear Information System (INIS)

    Objective: Based on the previous experience of using anti-androgen receptor triple helix forming oligonucleotide (TFO) to inhibit proliferation of prostate cancer cells, a 125I labeled TFO was prepared and tested in this experiment as an androgen receptor targeted antigene radiotherapy. Methods: 125I-TFO was labeled through Iodogen and then transfected LNCaP prostate cancer cells via liposome. The unlabeled TFO, 125I, and naturally cultured cells served as controls. The cellular proliferation was detected by methyl thiazolium tetrazolium (MTT) method, the expression of androgen receptor gene was carried out by RT-PCR and immunohistochemical study. Results: The radiolabeling efficiency, radiochemical purity and specific activity of 125I-TFO were 63.7%, 95.6% and 80.1 kBq/μg, respectively. At the same TFO concentration, the androgen receptor expression level in 125I-TFO treated cells was markedly lower than that of TFO group (P125I-TFO on cellular proliferation was significantly higher (P< 0.01). Conclusion: The inhibitory effect on androgen receptor expression and cell proliferation of prostate cancer cells of antigene therapy with radio-labeled TFO were significantly more obvious than that of classical antigene therapy. (authors)

  15. Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Mark N Stein; Neal Patel; Alexander Bershadskiy; Alisa Sokoloff; Eric A Singer

    2014-01-01

    Suppression of gonadal testosterone synthesis represents the standard ifrst line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer (CRPC), it is possible to detect persistent activation of the androgen receptor (AR) through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17α-hydroxylase and 17,20-lyase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a signiifcant improvement in overall survival (OS) with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone (ACTH), providing a rationale for development of CYP17 inhibitors with increased speciifcity for 17,20-lyase (orteronel, galeterone and VT-464) that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors;recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents;and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone beneift or restore abiraterone activity.

  16. Hot flushes in prostatic cancer patients during androgen-deprivation therapy with monthly dose of degarelix or leuprolide

    DEFF Research Database (Denmark)

    Iversen, P; Karup, C; van der Meulen, E;

    2011-01-01

    The aim of the study was to compare the onset, incidence and frequency/intensity of hot flushes during androgen-deprivation therapy with a gonadotropin-releasing hormone antagonist (GnRH) blocker versus an agonist using data from a randomized Phase 3 clinical trial. In total, 610 prostate cancer ...

  17. Relationship between prostate volume changes and treatment duration of neoadjuvant androgen deprivation during intensity-modulated radiation therapy for Japanese patients with prostate cancer.

    Science.gov (United States)

    Tomida, Masashi; Okudaira, Kuniyasu; Kamomae, Takeshi; Oguchi, Hiroshi; Miyake, Yoshikazu; Yoneda, Kazuo; Itoh, Yoshiyuki

    2016-08-01

    The application of neoadjuvant androgen deprivation (NAD) in prostate cancer leads to a reduction in prostate volume, and the trends in volume reduction differ according to the treatment duration of NAD. A reduction in volume during external beam radiation therapy may lead to the exposure of normal tissues to an unexpected dose. In fact, prostate volume reductions have primarily been reported in European and American institutions. Although the prostate volume of Japanese patients is known to be small, the trends in prostate volume change during radiation therapy remain unclear. In the present study, we aimed to evaluate the changes in prostate volume of Japanese patients during intensity-modulated radiation therapy (IMRT) with NAD. Nineteen Japanese patients with prostate cancer underwent IMRT with NAD. Kilovoltage computed tomography (CT) images were obtained for treatment planning and verification of the treatment position for each treatment fraction. The patients were divided into 3 groups based on the duration of NAD, as follows: NAD prostate volume reductions at the 36th treatment fraction, relative to the planning CT, were 7.8%, 2.0%, and 1.7% for the S-NAD, M-NAD, and L-NAD groups, respectively. Prostate volume shrunk greater in the S-NAD group than in the M-NAD and L-NAD groups; this finding was consistent with those of previous studies. The prostate volume changes in Japanese patients were smaller compared to those in European and American patients. PMID:27578915

  18. Neuroendocrine differentiation in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Jiaoti Huang

    2008-01-01

    @@ The treatment of choice for advanced/metastatic prostate cancer(PC) is hormonal therapy. Although patients respond initially to this therapy, the tumor will recur and enter the androgen-independent state, which is the major obstacle in therapy.

  19. Risk factors for bone loss with prostate cancer in Korean men not receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Sun-Ouck Kim

    2009-04-01

    Full Text Available PURPOSE: Preexisting bone loss in men with prostate cancer is an important issue due to the accelerated bone loss during androgen deprivation therapy (ADT. In addition, a high prostate-specific antigen (PSA level has been reported to be related to bone metabolism. This study assessed the factors associated with osteoporosis in Korean men with non-metastatic prostate cancer before undergoing ADT. MATERIAL AND METHODS: The study enrolled patients admitted for a prostate biopsy because of a high PSA or palpable nodule on a digital rectal examination. We divided the patients (n = 172 according to the results of the biopsy: group I, non-metastatic prostate cancer (n = 42 and group II, benign prostatic hypertrophy (BPH; n = 130. The lumbar bone mineral density (BMD was evaluated using quantitative computed tomography. The demographic, health status, lifestyle, body mass index (BMI, serum testosterone concentration, and disease variables in prostate cancer (Gleason score, clinical stage, and PSA were analyzed prospectively to determine their effect on the BMD. RESULTS: The estimated mean T-score was higher in group I than in group II (-1.96 ± 3.35 vs. -2.66 ± 3.20, but without statistic significance (p = 0.235. The significant factors correlated with BMD in group I were a high serum PSA (ß = -0.346, p = 0.010 and low BMI (ß = 0.345, p = 0.014 in the multiple linear regression model. Also old age (r = -0.481, p = 0.001, a high serum PSA (r = -0.571, p < 0.001, low BMI (r = 0.598, p < 0.001, and a high Gleason’s score (r = -0.319, p = 0.040 were the factors related to BMD in the correlation. The significant factors correlated with BMD in group II were old age (ß = -0.324, p = 0.001 and BMI (ß = 0.143, p = 0.014 in the multiple linear regression model. CONCLUSIONS: The risk factors for osteoporosis in men with prostate cancer include a low BMI, and elevated serum PSA. Monitoring BMD from the outset of ADT is a logical first step in the clinical

  20. Antivascular Effects of Neoadjuvant Androgen Deprivation for Prostate Cancer: An In Vivo Human Study Using Susceptibility and Relaxivity Dynamic MRI

    International Nuclear Information System (INIS)

    Purpose: The antivascular effects of androgen deprivation have been investigated in animal models; however, there has been minimal investigation in human prostate cancer. This study tested the hypothesis that androgen deprivation causes significant reductions in human prostate tumor blood flow and the induction of hypoxia at a magnitude and in a time scale relevant to the neoadjuvant setting before radiotherapy. Methods and Materials: Twenty patients were examined, each with five multi-parameter magnetic resonance imaging scans: two scans before the commencement of androgen suppression, one scan after 1 month of hormone treatment, and two further scans after 3 months of therapy. Quantitative parametric maps of the prostate informing on relative blood flow (rBF), relative blood volume (rBV), vascular permeability (transfer constant [Ktrans]), leakage space (ve) and blood oxygenation (intrinsic relaxivity [R2*]) were calculated. Results: Tumor blood volume and blood flow decreased by 83% and 79%, respectively, in the first month (p trans and 53% for ve By 3 months, significant increases in R2* had occurred in prostate tumor, with a rise of 41.1% (p 2* in regions of prostate cancer and a decrease in blood volume suggest a reduction in tumor oxygenation.

  1. PROGNOSTIC VALUE OF THE BASELINE VALUES OF SERUM TESTOSTERONE AND FREE ANDROGEN INDEX IN PATIENTS WITH PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    M. E. Grigoryev

    2012-01-01

    Full Text Available The growing incidence of prostate cancer (PC and its variable nature are an important problem today. PC is distinguished by its latent ability in many cases, which makes its screening difficult.Prostate-specific antigen (PSA is one of the most common tumor markers of PC, which are used for mass male screening. However, the detection rate of PC in men with normal PSA values is also very high. This promotes an active search for new markers and predictors of PC.The effect of androgens on hormonal carcinogenesis in the prostate suggests that the analysis of serum testosterone concentrations and free androgen index may be made in patients with low PSA levels in the early diagnosis and prognosis of PC.

  2. Variation in Use of Androgen Suppression With External-Beam Radiotherapy for Nonmetastatic Prostate Cancer

    International Nuclear Information System (INIS)

    Purpose: To describe practice patterns associated with androgen suppression (AS) stratified by disease risk group in patients undergoing external-beam radiotherapy (EBRT) for localized prostate cancer. Methods and Materials: We identified 2,184 low-risk, 2,339 intermediate-risk, and 2,897 high-risk patients undergoing EBRT for nonmetastatic prostate cancer diagnosed between January 1, 2004, and December 31, 2005, in the linked Surveillance, Epidemiology, and End Results—Medicare database. We examined the association of patient, clinical, and demographic characteristics with AS use by multivariate logistic regression. Results: The proportions of patients receiving AS for low-risk, intermediate-risk, and high-risk prostate cancer were 32.2%, 56.3%, and 81.5%, respectively. AS use among men in the low-risk disease category varied widely, ranging from 13.6% in Detroit to 47.8% in Kentucky. We observed a significant decline in AS use between 2004 and 2005 within all three disease risk categories. Men aged ≥75 years or with elevated comorbidity levels were more likely to receive AS. Conclusion: Our results identified apparent overuse and underuse of AS among men within the low-risk and high-risk disease categories, respectively. These results highlight the need for clinician and patient education regarding the appropriate use of AS. Practice patterns among intermediate-risk patients reflect the clinical heterogeneity of this population and underscore the need for better evidence to guide the treatment of these patients.

  3. Variation in Use of Androgen Suppression With External-Beam Radiotherapy for Nonmetastatic Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Swisher-McClure, Samuel, E-mail: Swisher-Mcclure@uphs.upenn.edu [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Pollack, Craig E. [Division of General Internal Medicine, Johns Hopkins University School of Medicine and Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (United States); Christodouleas, John P. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Guzzo, Thomas J. [Department of Surgery, Division of Urology, University of Pennsylvania, Philadelphia, PA (United States); Haas, Naomi B. [Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Vapiwala, Neha [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Bekelman, Justin E. [Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA (United States); Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA (United States); Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, PA (United States)

    2012-05-01

    Purpose: To describe practice patterns associated with androgen suppression (AS) stratified by disease risk group in patients undergoing external-beam radiotherapy (EBRT) for localized prostate cancer. Methods and Materials: We identified 2,184 low-risk, 2,339 intermediate-risk, and 2,897 high-risk patients undergoing EBRT for nonmetastatic prostate cancer diagnosed between January 1, 2004, and December 31, 2005, in the linked Surveillance, Epidemiology, and End Results-Medicare database. We examined the association of patient, clinical, and demographic characteristics with AS use by multivariate logistic regression. Results: The proportions of patients receiving AS for low-risk, intermediate-risk, and high-risk prostate cancer were 32.2%, 56.3%, and 81.5%, respectively. AS use among men in the low-risk disease category varied widely, ranging from 13.6% in Detroit to 47.8% in Kentucky. We observed a significant decline in AS use between 2004 and 2005 within all three disease risk categories. Men aged {>=}75 years or with elevated comorbidity levels were more likely to receive AS. Conclusion: Our results identified apparent overuse and underuse of AS among men within the low-risk and high-risk disease categories, respectively. These results highlight the need for clinician and patient education regarding the appropriate use of AS. Practice patterns among intermediate-risk patients reflect the clinical heterogeneity of this population and underscore the need for better evidence to guide the treatment of these patients.

  4. ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients.

    Science.gov (United States)

    Baena, Esther; Shao, Zhen; Linn, Douglas E; Glass, Kimberly; Hamblen, Melanie J; Fujiwara, Yuko; Kim, Jonghwan; Nguyen, Minh; Zhang, Xin; Godinho, Frank J; Bronson, Roderick T; Mucci, Lorelei A; Loda, Massimo; Yuan, Guo-Cheng; Orkin, Stuart H; Li, Zhe

    2013-03-15

    Distinguishing aggressive from indolent disease and developing effective therapy for advanced disease are the major challenges in prostate cancer research. Chromosomal rearrangements involving ETS transcription factors, such as ERG and ETV1, occur frequently in prostate cancer. How they contribute to tumorigenesis and whether they play similar or distinct in vivo roles remain elusive. Here we show that in mice with ERG or ETV1 targeted to the endogenous Tmprss2 locus, either factor cooperated with loss of a single copy of Pten, leading to localized cancer, but only ETV1 appeared to support development of invasive adenocarcinoma under the background of full Pten loss. Mechanistic studies demonstrated that ERG and ETV1 control a common transcriptional network but largely in an opposing fashion. In particular, while ERG negatively regulates the androgen receptor (AR) transcriptional program, ETV1 cooperates with AR signaling by favoring activation of the AR transcriptional program. Furthermore, we found that ETV1 expression, but not that of ERG, promotes autonomous testosterone production. Last, we confirmed the association of an ETV1 expression signature with aggressive disease and poorer outcome in patient data. The distinct biology of ETV1-associated prostate cancer suggests that this disease class may require new therapies directed to underlying programs controlled by ETV1.

  5. Monotherapy of androgen deprivation therapy versus radical prostatectomy among veterans with localized prostate cancer: comparative effectiveness analysis of retrospective cohorts

    Directory of Open Access Journals (Sweden)

    Liu J

    2012-05-01

    Full Text Available Jinan Liu1,2, Lizheng Shi1,2,3, Oliver Sartor31Tulane University, School of Public Health and Tropical Medicine, 2Southeast Louisiana Veterans Health Care System, Tulane University, 3School of Medicine and Tulane Cancer Center, New Orleans, LA, USABackground: This retrospective cohort study aimed to examine the comparative effectiveness of monotherapy of primary androgen deprivation therapy or radical prostatectomy.Methods: Male patients with localized prostate cancer (T1-T2, N0, M0 were identified in the Veterans Affairs Veterans Integrated Service Network 16 data warehouse (January 2003 to June 2006, with one-year baseline and at least three-year follow-up data (until June 2009. Patients were required to be 18–75 years old and without other recorded cancer history. The initiation of primary androgen deprivation therapy or monotherapy of radical prostatectomy within six months after the first diagnosis of prostate cancer was used as the index date. Primary androgen deprivation therapy patients were matched to the radical prostatectomy patients via propensity score, which was predicted from a logistic regression of treatment selection (primary androgen deprivation therapy versus radical prostatectomy on age, race, marital status, insurance type, cancer stage, Charlson comorbidity index, and alcohol and tobacco use. The overall survival from initiation of index treatment was then analyzed using the Kaplan–Meier and Cox proportional hazards model.Results: The two cohorts were well matched at baseline (all P > 0.05. During a median follow-up of 4.3 years, the cumulative incidence of death was 13 (10.57% among 123 primary androgen deprivation therapy patients and four (3.25% among 123 radical prostatectomy patients (P < 0.05. The overall three-year survival rate was 92.68% for primary androgen deprivation therapy and 98.37% for radical prostatectomy (P < 0.05. Patients who received primary androgen deprivation therapy had almost three times as

  6. Favorable outcomes in locally advanced and node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy

    International Nuclear Information System (INIS)

    The most appropriate treatment for men with prostate cancer and positive pelvic nodes, N+, is an area of active controversy. We report our 5-years outcomes in men with locally advanced prostate cancer (T1-T4N0-N1M0) treated with definitive radiotherapy encompassing the prostate and pelvic lymph nodes (intensity modulated radiotherapy, IMRT) and long-term androgen deprivation therapy (ADT). Of the 138 consecutive eligible men all living patients have been followed up to almost 5 years. Survival endpoints for 5-year biochemical failure-free survival (BFFS), relapse-free survival (RFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were assessed by Kaplan-Meier analysis. Univariate and multivariate Cox regression proportional hazards models were constructed for all survival endpoints. The RTOG morbidity grading system for physician rated toxicity was applied. Patients with locally advanced T3-T4 tumors (35 %) and N1 (51 %) have favorable outcome when long-term ADT is combined with definitive radiotherapy encompassing pelvic lymph nodes. The 5-year BFFS, RFS, PCSS and OS were 71.4, 76.2, 94.5 and 89.0 %, respectively. High Gleason sum (9–10) had a strong independent prognostic impact on BFFS, RFS and OS (p = 0.001, <0.001, and 0.005 respectively). The duration of ADT (= > 28 months) showed a significant independent association with improved PCSS (p = 0.02) and OS (p = 0.001). Lymph node involvement was not associated with survival endpoints in the multivariate analysis. The radiotherapy induced toxicity seen in our study population was moderate with rare Grade 3 GI side effects and up to 11 % for Grade 3 GU consisting mainly of urgency and frequency. Pelvic IMRT in combination with long-term ADT can achieve long-lasting disease control in men with N+ disease and unfavorable prognostic factors. The online version of this article (doi:10.1186/s13014-015-0540-3) contains supplementary material, which is available to authorized users

  7. Influence of immune inflammation on androgen receptor expression in benign prostatic hyperplasia tissue

    Institute of Scientific and Technical Information of China (English)

    Zong-Lin Wu; Ya Yuan; He Geng; Shu-Jie Xia

    2012-01-01

    This study was designed to investigate the association between immune inflammation and androgen receptor (AR) expression in benign prostatic hyperplasia (BPH).We retrospectively analyzed 105 prostatectomy specimens.An immune inflammation score for each specimen was defined by combining three immunohistochemical markers (CD4,CD8 and CD20).The immunohistochemical markers were CD4 and CD8 for T lymphocytes,CD20 for B lymphocytes and AR antibody for the AR in BPH samples.Rates of CD4,CD8,CD20 and AR expression in BPH were 20 (19.0%),21 (20.0%),101 (96.2%) and 48 (45.7%),respectively.Total prostate volume (TPV) was higher in the immune inflammation group than in the non-immune inflammation group (62.7 ml vs.49.2 ml,t=2.482,P<0.05).Patients in the immune inflammation group had a higher serum prostate-specific antigen (PSA) than those in the non-inflammation group (7.5 ng ml-1 vs.5.4 ng ml-1,t=2.771,P<0.05).Specifically,the immune inflammation group showed a higher rate of AR expression than the non-inflammation group (56.1% vs.28.2%,x2=7.665,P<0.05).Our study revealed a strong association between immune inflammation and TPV,serum PSA and AR expression in BPH tissue.Prostate hyperplasia caused by an immune inflammatory process may contribute to BPH progression over time.Therefore,the inflammatory response involved in BPH may be a prime therapeutic target.

  8. Maximal androgen blockade versus castration alone in patients with metastatic prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Abeer A.Mahmoud; Eman A.El-Sharawy; Mohamed M.El-Bassiouny; Ramy R.Ghali

    2014-01-01

    Objective: Maximum androgen blockade (MAB), consisting of an antiandrogen plus either a luteinizing hormone-releasing hormone agonist (LHRHA) or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB (orchiectomy or LHRHA “Goserelin”) and anti-androgen “Bicalutamide” with castration alone (orchiectomy or LHRHA) in previ-ously untreated metastatic prostate cancer patients.Methods: Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot.Results: During the period from January 2011 to January 2013, with a median folow up of 18 months (range 6 to 24 months), there were eight deaths (16%), in MAB arm and ten deaths (20%) in castration alone arm. At three months, there were 35 patients (70%) with prostate specific antigen (PSA) normalization (≤ 4 mg/dL) in MAB arm versus 17 patients (34%) with PSA normalization in castration alone arm (P = 0.001). The median progression free survival (PFS) times were 22.18 months (95% CI, 19.7 to 24.2 months) for MAB arm versus 22 months in castration alone arm (95% CI, 18 to 25.9 months;P = 0.045). The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm (P > 0.05). The median overal survival (OS) was not reached in either arm. Both hematological

  9. The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maryam Ghotbaddini

    2015-07-01

    Full Text Available The reported biological effects of TCDD include induction of drug metabolizing enzymes, wasting syndrome and tumor promotion. TCDD elicits most of its effects through binding the aryl hydrocarbon receptor (AhR. TCDD induced degradation of AhR has been widely reported and requires ubiquitination of the protein. The rapid depletion of AhR following TCDD activation serves as a mechanism to modulate AhR mediated gene induction. In addition to inducing AhR degradation, TCDD has been reported to induce degradation of hormone receptors. The studies reported here, evaluate the effect of TCDD exposure on androgen receptor (AR expression and activity in androgen-sensitive LNCaP and castration-resistant C4-2 prostate cancer cells. Our results show that TCDD exposure does not induce AhR or AR degradation in C4-2 cells. However, both AhR and AR are degraded in LNCaP cells following TCDD exposure. In addition, TCDD enhances AR phosphorylation and induces expression of AR responsive genes in LNCaP cells. Our data reveals that TCDD effect on AR expression and activity differs in androgen-sensitive and castration-resistant prostate cancer cell models.

  10. CSF1 Receptor Targeting In Prostate Cancer Reverses Macrophage-Mediated Resistance To Androgen Blockade Therapy

    Science.gov (United States)

    Escamilla, Jemima; Schokrpur, Shiruyeh; Liu, Connie; Priceman, Saul J.; Moughon, Diana; Jiang, Ziyue; Pouliot, Frederic; Magyar, Clara; Sung, James L.; Xu, Jingying; Deng, Gang; West, Brian L.; Bollag, Gideon; Fradet, Yves; Lacombe, Louis; Jung, Michael E.; Huang, Jiaoti; Wu, Lily

    2015-01-01

    Growing evidence suggests that tumor-associated macrophages (TAMs) promote cancer progression and therapeutic resistance by enhancing angiogenesis, matrix-remodeling and immunosuppression. In this study prostate cancer (PCa) under androgen blockade therapy (ABT) was investigated, demonstrating that TAMs contribute to PCa disease recurrence through paracrine signaling processes. ABT induced the tumor cells to express macrophage colony-stimulating factor 1 (M-CSF-1 or CSF-1) and other cytokines that recruit and modulate macrophages, causing a significant increase in TAM infiltration. Inhibitors of CSF-1 signaling through its receptor, CSF-1R, were tested in combination with ABT, demonstrating that blockade of TAM influx in this setting disrupts tumor promotion and sustains a more durable therapeutic response compared to ABT alone. PMID:25736687

  11. Football training in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, Jacob; Hornstrup, Therese; Christensen, Jesper F;

    2016-01-01

    PURPOSE: To investigate the activity profile of football training and its short-term effects on bone mass, bone turnover markers (BTMs) and postural balance in men with prostate cancer (PCa) undergoing androgen deprivation therapy (ADT). METHODS: This was a randomised 12-week study in which men...... with PCa undergoing ADT were assigned to a football intervention group [FTG, n = 29, 67 ± 7 (±SD) years] training 2‒3 times per week for 45‒60 min or to a control group (n = 28, 66 ± 5 years). The activity profile was measured using a 5-Hz GPS. The outcomes were total body and leg bone mineral content (BMC...... between-group differences in favour of FTG in total body BMC [26.4 g, 95 % confidence interval (CI): 5.8-46.9 g, p = 0.013], leg BMC (13.8 g, 95 % CI: 7.0‒20.5 g, p

  12. One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

    Science.gov (United States)

    Corbin, Joshua M.; Ruiz-Echevarría, Maria J.

    2016-01-01

    Cancer cell metabolism differs significantly from the metabolism of non-transformed cells. This altered metabolic reprogramming mediates changes in the uptake and use of nutrients that permit high rates of proliferation, growth, and survival. The androgen receptor (AR) plays an essential role in the establishment and progression of prostate cancer (PCa), and in the metabolic adaptation that takes place during this progression. In its role as a transcription factor, the AR directly affects the expression of several effectors and regulators of essential catabolic and biosynthetic pathways. Indirectly, as a modulator of the one-carbon metabolism, the AR can affect epigenetic processes, DNA metabolism, and redox balance, all of which are important factors in tumorigenesis. In this review, we focus on the role of AR-signaling on one-carbon metabolism in tumorigenesis. Clinical implications of one-carbon metabolism and AR-targeted therapies for PCa are discussed in this context. PMID:27472325

  13. CACUL1 functions as a negative regulator of androgen receptor in prostate cancer cells.

    Science.gov (United States)

    Choi, Hanbyeul; Lee, Sang Hyup; Um, Soo-Jong; Kim, Eun-Joo

    2016-07-01

    The androgen receptor (AR) plays a critical role in the initiation and progression of prostate cancer (PCa), and thus its regulation is an important tool in PCa therapy. Here, we report that CDK2-associated cullin 1 (CACUL1) directly associates with AR and suppresses AR transcriptional activity. In addition, CACUL1 represses histone demethylase LSD1-mediated AR transactivation by competing with LSD1 for AR binding. Depletion of CACUL1 enhances the LSD1 occupancy of the AR-target promoter, accompanied by decreased accumulation of H3K9me2, a repressive transcriptional marker. CACUL1 and LSD1 oppositely regulate CDX-induced cell death in AR-positive LNCaP and metastatic castrate-resistant LNCaP-LN3 cells. These data suggest that CACUL1 impairs LSD1-mediated activation of AR, thereby implicating it as a potential antitumor target in PCa. PMID:27085459

  14. MicroPET assessment of androgenic control of glucose and acetate uptake in the rat prostate and a prostate cancer tumor model

    International Nuclear Information System (INIS)

    PET has been used to monitor changes in tumor metabolism in breast cancer following hormonal therapy. This study was undertaken to determine whether PET imaging could evaluate early metabolic changes in prostate tumor following androgen ablation therapy. Studies were performed comparing two positron-emitting tracers, 18F-FDG and 11C-acetate, in Sprague-Dawley male rats to monitor metabolic changes in normal prostate tissue. Additional studies were performed in nude mice bearing the CWR22 androgen-dependent human prostate tumor to evaluate metabolic changes in prostate tumor. In rats, for the androgen ablation pretreatment, 1 mg diethylstilbestrol (DES) was injected subcutaneously 3 and 24 hours before tracer injection. For androgen pretreatment, 500 μg dihydrotestosterone (DHT) was injected intraperitoneally 2 and 6 hours before tracer injection. The rats were divided into three groups, Group A (no-DES, no-DHT, n = 18), Group B (DES, no-DHT, n = 18) and Group C (DES, DHT, n = 18). In each group, 10 animals received 18F-FDG, whereas the remaining eight animals were administered 11C-acetate. Rats were sacrificed at 120 min post-injection of 18F-FDG or 30 min post-injection of 11C-acetate. Pretreatment of the mouse model using DHT (200 μg of DHT in 0.1 mL of sunflower seed oil) or DES (200 μg of DES in 0.1 mL of sunflower seed oil) was conducted every 2 days for one week. Mice were imaged with both tracers in the microPET scanner (Concorde Microsystems Inc.). DES treatment caused a decrease in acetate and glucose metabolism in the rat prostate. Co-treatment with DHT maintained the glucose metabolism levels at baseline values. In the tumor bearing mice, similar effects were seen in 18F-FDG study, while there was no significant difference in 11C-acetate uptake. These results indicate that changes in serum testosterone levels influence 18F-FDG uptake in the prostate gland, which is closely tied to glucose metabolism, within 24 hours of treatment and in the prostate

  15. Inhibition of Apoptosis in Prostate Cancer Cells by Androgens Is Mediated through Downregulation of c-Jun N-terminal Kinase Activation

    Directory of Open Access Journals (Sweden)

    Petra Isabel Lorenzo

    2008-05-01

    Full Text Available Androgen deprivation induces the regression of prostate tumors mainly due to an increase in the apoptosis rate; however, the molecular mechanisms underlying the antiapoptotic actions of androgens are not completely understood. We have studied the antiapoptotic effects of androgens in prostate cancer cells exposed to different proapoptotic stimuli. Terminal deoxynucleotidyl transferase-mediated nick-end labeling and nuclear fragmentation analyses demonstrated that androgens protect LNCaP prostate cancer cells from apoptosis induced by thapsigargin, the phorbol ester 12-O-tetradecanoyl-13-phorbol-acetate, or UV irradiation. These three stimuli require the activation of the c-Jun N-terminal kinase (JNK pathway to induce apoptosis and in all three cases, androgen treatment blocks JNK activation. Interestingly, okadaic acid, a phosphatase inhibitor that causes apoptosis in LNCaP cells, induces JNK activation that is also inhibited by androgens. Actinomycin D, the antiandrogen bicalutamide or specific androgen receptor (AR knockdown by small interfering RNA all blocked the inhibition of JNK activation mediated by androgens indicating that this activity requires AR-dependent transcriptional activation. These data suggest that the crosstalk between AR and JNK pathways may have important implications in prostate cancer progression and may provide targets for the development of new therapies.

  16. Systematic structure-function analysis of androgen receptor Leu 701 mutants explains the properties of the prostate cancer mutant L701H

    NARCIS (Netherlands)

    D.J. van de Wijngaart (Dennis); M. Molier; S.J. Lusher (Scott); R. Hersmus (Remko); G.W. Jenster (Guido); J. Trapman (Hans); H.J. Dubbink (Erik Jan)

    2010-01-01

    textabstractOne mechanism of prostate tumors for escape from androgen ablation therapies is mutation of the androgen receptor (AR). Weinvestigated the unique properties of theARL701H mutant, which is strongly stimulated by cortisol, by a systematic structure-function analysis. Most amino acid substi

  17. Impact of Concurrent Androgen Deprivation on Fiducial Marker Migration in External-beam Radiation Therapy for Prostate Cancer

    International Nuclear Information System (INIS)

    Purpose: To determine the extent of gold fiducial marker (FM) migration in patients treated for prostate cancer with concurrent androgen deprivation and external-beam radiation therapy (EBRT). Methods and Materials: Three or 4 gold FMs were implanted in 37 patients with prostate adenocarcinoma receiving androgen deprivation therapy (ADT) in conjunction with 70-78 Gy. Androgen deprivation therapy was started a median of 3.9 months before EBRT (range, 0.3-12.5 months). To establish the extent of FM migration, the distance between each FM was calculated for 5-8 treatments once per week throughout the EBRT course. For each treatment, the distance between FMs was compared with the distance from the digitally reconstructed radiographs generated from the planning CT. A total of 281 treatments were analyzed. Results: The average daily migration was 0.8 ± 0.3 mm, with distances ranging from 0.2 mm-2.6 mm. Two of the 281 assessed treatments (0.7%) showed migrations >2 mm. No correlation between FM migration and patient weight or time delay between ADT and start of EBRT was found. There was no correlation between the extent of FM migration and prostate volume. Conclusion: This is the largest report of implanted FM migration in patients receiving concomitant ADT. Only 0.7% of the 281 treatments studied had significant marker migrations (>2 mm) throughout the course of EBRT. Consequently, the use of implanted FMs in these patients enables accurate monitoring of prostate gland position during treatment.

  18. Inhibition of human prostate cancer xenograft growth by 125I labeled triple-helin forming oligonucleotide directed against androgen receptor

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yong; MA Yi; LU Han-ping; GAO Jin-hui; LIANG Chang-sheng; LIU Chang-zheng; ZOU Jun-tao; WANG Hua-qiao

    2008-01-01

    Background The failure of hormone treatment for advanced prostate cancer might be related to aberrant activation of the androgen receptor.We have shown that 125I labeled triple-helix forming oligonucleotide (TFO) against the androgen receptor gene inhibits androgen receptor expression and cell proliferation of LNCaP prostate cancer cells in vitro.This study aimed at exploring the effects of the 125I-TFO on prostate tumor growth in vivo using a nude mouse xenograft model.Methods TFO was labeled with 125I by the iodogen method.Thirty-two nude mice bearing LNCaP xenograft tumors were randomized into 4 groups and were intratumorally injected with 125I-TFO,unlabeled TFO,Na125I and normal saline.Tumor size was measured weekly.The tumor growth inhibition rate (RI) was calculated by measurement of tumor weight.The expression of the androgen receptor gene was performed by RT-PCR and immunohistochemical study.The prostate specific antigen (PSA) serum levels were measured by enzyme linked immunosorbent assay.The tumor cell apoptosis index (Al) was detected by TUNEL assay.Results Tumor measurements showed that tumor development was significantly inhibited by either 125I-TFO or TFO,with tumor RIs of 50.79% and 32.80% respectively.125I-TFO caused greater inhibition of androgen receptor expression and higher Als in tumor tissue than TFO.Both the tumor weight and the PSA serum levels in 125I-TFO treated mice ((0.93±0.15) g and (17.43±1.85) ng/ml,respectively) were significantly lower than those ((1.27±0.21) g and (28.25±3.41)ng/ml,respectively) in TFO treated mice (all P<0.05).Na125I did not significantly affect tumor growth and androgen receptor expression in tumor tissue.Conclusions The 125I-TFO can effectively inhibit androgen receptor expression and tumor growth of human prostate cancer xenografts in vivo.The inhibitory efficacy of 125I-TFO is more potent than that of TFO,providing a reference for future studies of antigen radiotherapy.

  19. Androgen Deprivation Therapy and Secondary Hormone Therapy in the Management of Hormone-sensitive and Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Saad, Fred; Fizazi, Karim

    2015-11-01

    Androgen deprivation therapy (ADT) is the standard of care for patients with metastatic prostate cancer (mPC). However, nearly all patients with mPC progress to castration-resistant PC (CRPC). Arrays of treatments, including secondary hormonal therapies, are available for the treatment of mPC and CRPC, which show efficacy when administered with ADT. Continuation of ADT is recommended for CRPC treatment as therapies are added. New secondary hormonal therapies include abiraterone, targeting the CYP17 enzyme family, and enzalutamide, an androgen receptor inhibitor with heightened binding specificity. The optimal decision-making process for CRPC treatment option remains unclear, pending further research and experience. PMID:26282624

  20. A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy

    International Nuclear Information System (INIS)

    Androgen deprivation therapy (ADT) is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT. A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data. Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant impact on reducing the risk of fracture, promoting physical

  1. A pilot study of exercise in men with prostate cancer receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Lee C

    2012-03-01

    Full Text Available Abstract Background Androgen deprivation therapy (ADT is the mainstay therapy for men with prostate cancer. However, there are musculoskeletal side effects from ADT that increase the risk for osteoporosis and fracture, and can compromise the quality of life of these individuals. The objectives of this study are to determine the efficacy of a home-based walking exercise program in promoting bone health, physical function and quality of life in men with prostate cancer receiving ADT. Methods/Design A 12-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Sixty men with prostate cancer who will be starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 12-month home-based walking exercise program, while the Control Group will receive standard medical advice from the attending physician. A number of outcome measures will be used to assess bone health, physical function, and health-related quality of life. At baseline and 12 months, bone health will be assessed using dual-energy X-ray absorptiometry. At baseline and every 3 months up to 12 months, physical function will be evaluated using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale, Activities-specific Balance Confidence Scale, Short Physical Performance Battery, and Six-Minute Walk Test; and health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy Prostate Module and the Medical Outcomes Study 12-item Short Form Health Survey Version 2. A mixed multiple analysis of variance will be used to analyze the data. Discussion Musculoskeletal health management remains a challenge in men with prostate cancer receiving ADT. This study addresses this issue by designing a simple and accessible home-based walking exercise program that will potentially have significant

  2. Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Zumsteg, Zachary S.; Spratt, Daniel E.; Pei, Xin; Yamada, Yoshiya; Kalikstein, Abraham [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Kuk, Deborah; Zhang, Zhigang [Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Zelefsky, Michael J., E-mail: zelefskm@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-03-15

    Purpose: We investigated the benefit of short-term androgen-deprivation therapy (ADT) in patients with intermediate-risk prostate cancer (PC) receiving dose-escalated external beam radiation therapy. Methods and Materials: The present retrospective study comprised 710 intermediate-risk PC patients receiving external beam radiation therapy with doses of ≥81 Gy at a single institution from 1992 to 2005, including 357 patients receiving neoadjuvant and concurrent ADT. Prostate-specific antigen recurrence-free survival (PSA-RFS) and distant metastasis (DM) were compared using the Kaplan-Meier method and Cox proportional hazards models. PC-specific mortality (PCSM) was assessed using competing-risks analysis. Results: The median follow-up was 7.9 years. Despite being more likely to have higher PSA levels, Gleason score 4 + 3 = 7, multiple National Comprehensive Cancer Network intermediate-risk factors, and older age (P≤.001 for all comparisons), patients receiving ADT had improved PSA-RFS (hazard ratio [HR], 0.598; 95% confidence interval [CI], 0.435-0.841; P=.003), DM (HR, 0.424; 95% CI, 0.219-0.819; P=.011), and PCSM (HR, 0.380; 95% CI, 0.157-0.921; P=.032) on univariate analysis. Using multivariate analysis, ADT was an even stronger predictor of improved PSA-RFS (adjusted HR [AHR], 0.516; 95% CI, 0.360-0.739; P<.001), DM (AHR, 0.347; 95% CI, 0.176-0.685; P=.002), and PCSM (AHR, 0.297; 95% CI, 0.128-0.685; P=.004). Gleason score 4 + 3 = 7 and ≥50% positive biopsy cores were other independent predictors of PCSM. Conclusions: Short-term ADT improves PSA-RFS, DM, and PCSM in patients with intermediate-risk PC undergoing dose-escalated external beam radiation therapy.

  3. Androgen deprivation of prostate cancer: Leading to a therapeutic dead end.

    Science.gov (United States)

    Katzenwadel, Arndt; Wolf, Philipp

    2015-10-10

    Androgen deprivation therapy (ADT) is considered as the standard therapy for men with de novo or recurrent metastatic prostate cancer. ADT commonly leads to initial biochemical and clinical responses. However, several months after the beginning of treatment, tumors become castration-resistant and virtually all patients show disease progression. At this stage, tumors are no longer curable and cancer treatment options are only palliative. In this review, we describe molecular alterations in tumor cells during ADT, which lead to deregulation of different signaling pathways and castration-resistance, and how they might interfere with the clinical outcome of different second-line therapeutics. A recent breakthrough finding that early chemotherapy is associated with a significant survival benefit in metastatic hormone-sensitive disease highlights the fact that there is time for a fundamental paradigm shift in the treatment of advanced prostate cancer. Therapeutic intervention seems to be indicated before a castration-resistant stage is reached to improve therapeutic outcome and to reduce undesirable side effects. PMID:26185001

  4. Acidic-phosphoprotein phosphatase activity of rat ventral prostate nuclei: apparent lack of effect of androgens.

    Science.gov (United States)

    Wilson, M J; Ahmed, K; Fischbach, T J

    1978-08-01

    A protein phosphatase activity has been demonstrated in nuclei of rat ventral prostate utilizing 32P-labelled phosvitin as a model acidic phosphoprotein substrate. This phosphoprotein phosphatase has a pH optimum of 6.7, is unaffected by the sulphydryl protecting agent 2-mercaptoethanol, and requires a divalent cation for maximal activity. Of the various divalent cations tested, Mg2+ is the most effective in reactivating the EDTA-inhibited enzyme. The phosphatase is inhibited by sodium flouride, sodium oxalate, N-ethylmaleimide, ATP and ADP but is relatively insensitive to ammonium molybdate. Increased ionic strength of the reaction medium also causes a reduction in the enzyme activity, e.g., by 48% at 200 mM sodium chloride. The activity of the acidic phosphoprotein phosphatase did not change significantly at 48 h or 96 h post-orchiectomy when expressed per unit of nuclear protein. However, it is reduced by approx. 30% at these times after castration if based on DNA content. The decline in activity per nucleus reflects the decrease in the realtive nuclear protein content observed at 48 h or 96 h post-orchiectomy. This suggests that the decline in the phosphorylation of prostatic nuclear acidic proteins which occurs upon androgen withdrawal is not due to increased nuclear phosphatase activity.

  5. Antiproliferation effects of an androgen receptor triple-helix forming oligonucleotide on prostate cancer cells

    International Nuclear Information System (INIS)

    Objective: To provide experimental basis for antigene radiation therapy through exploring the effects of antigene strategy on androgen receptor (AR) expression and proliferation of prostate cancer cells. Methods: The triple-helix forming oligonucleotide (TFO) targeting 2447-2461nt of AR cDNA was designed and transfected LNCaP prostate cancer cells with liposome. 24-72 h after transfection, the cellular proliferation was detected by 3H-thymidine (TdR) incorporation test, the expression of AR gene was examined by reverse transcription-polymerase chain reaction (RT-PCR) and expression of AR protein was performed by radioligand binding assay. The results of TFO were compared with antisense oligonucleotide (ASON). Results: At all time points, the AR expression levels in TFO group were markedly lower than that of ASON group (P<0.05). The inhibitory rate of TFO for cellular proliferation was significantly higher than that of ASON (P<0.05). Conclusion: The TFO was a potent inhibitor for AR expression and cell proliferation of LNCaP cells , and could be used in antigene radiotherapy. (authors)

  6. Catalytic inhibitors of DNA topoisomerase II suppress the androgen receptor signaling and prostate cancer progression.

    Science.gov (United States)

    Li, Haolong; Xie, Ning; Gleave, Martin E; Dong, Xuesen

    2015-08-21

    Although the new generation of androgen receptor (AR) antagonists like enzalutamide (ENZ) prolong survival of metastatic castration-resistant prostate cancer (CRPC), AR-driven tumors eventually recur indicating that additional therapies are required to fully block AR function. Since DNA topoisomerase II (Topo II) was demonstrated to be essential for AR to initiate gene transcription, this study tested whether catalytic inhibitors of Topo II can block AR signaling and suppress ENZ-resistant CRPC growth. Using multiple prostate cancer cell lines, we showed that catalytic Topo II inhibitors, ICRF187 and ICRF193 inhibited transcription activities of the wild-type AR, mutant ARs (F876L and W741C) and the AR-V7 splice variant. ICRF187 and ICRF193 decreased AR recruitment to target promoters and reduced AR nuclear localization. Both ICRF187 and ICRF193 also inhibited cell proliferation and delayed cell cycling at the G2/M phase. ICRF187 inhibited tumor growth of castration-resistant LNCaP and 22RV1 xenografts as well as ENZ-resistant MR49F xenografts. We conclude that catalytic Topo II inhibitors can block AR signaling and inhibit tumor growth of CRPC xenografts, identifying a potential co-targeting approach using these inhibitors in combination with AR pathway inhibitors in CRPC.

  7. Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression.

    Science.gov (United States)

    Komura, Kazumasa; Jeong, Seong Ho; Hinohara, Kunihiko; Qu, Fangfang; Wang, Xiaodong; Hiraki, Masayuki; Azuma, Haruhito; Lee, Gwo-Shu Mary; Kantoff, Philip W; Sweeney, Christopher J

    2016-05-31

    The androgen receptor (AR) plays an essential role in prostate cancer, and suppression of its signaling with androgen deprivation therapy (ADT) has been the mainstay of treatment for metastatic hormone-sensitive prostate cancer for more than 70 y. Chemotherapy has been reserved for metastatic castration-resistant prostate cancer (mCRPC). The Eastern Cooperative Oncology Group-led trial E3805: ChemoHormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) showed that the addition of docetaxel to ADT prolonged overall survival compared with ADT alone in patients with metastatic hormone-sensitive prostate cancer. This finding suggests that there is an interaction between AR signaling activity and docetaxel sensitivity. Here we demonstrate that the prostate cancer cell lines LNCaP and LAPC4 display markedly different sensitivity to docetaxel with AR activation, and RNA-seq analysis of these cell lines identified KDM5D (lysine-specific demethylase 5D) encoded on the Y chromosome as a potential mediator of this sensitivity. Knocking down KDM5D expression in LNCaP leads to docetaxel resistance in the presence of dihydrotestosterone. KDM5D physically interacts with AR in the nucleus, and regulates its transcriptional activity by demethylating H3K4me3 active transcriptional marks. Attenuating KDM5D expression dysregulates AR signaling, resulting in docetaxel insensitivity. KDM5D deletion was also observed in the LNCaP-derived CRPC cell line 104R2, which displayed docetaxel insensitivity with AR activation, unlike parental LNCaP. Dataset analysis from the Oncomine database revealed significantly decreased KDM5D expression in CRPC and poorer prognosis with low KDM5D expression. Taking these data together, this work indicates that KDM5D modulates the AR axis and that this is associated with altered docetaxel sensitivity. PMID:27185910

  8. Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

    DEFF Research Database (Denmark)

    Hvid, Thine; Winding, Kamilla; Rinnov, Anders;

    2013-01-01

    Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine me...... and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P...

  9. Effects of competitive and noncompetitive 5α-reductase inhibitors on serum and intra-prostatic androgens in beagle dogs

    Institute of Scientific and Technical Information of China (English)

    ZHAO Xiao-feng; YANG Yong; WANG Wei; QIU Zhi; ZHANG Peng; WANG Biao

    2013-01-01

    Background 5α-Reductase inhibitors (5α-RI) act by inhibiting the conversion of testosterone to dihydrotestosterone (DHT),thereby preventing DHT induced benign prostatic hyperplasia.The existing 5α-RIs can be classified into two types:competitive and noncompetitive.Currently,limited evidence is available concerning the effect differences between the two types of 5α-RI on androgens.The purpose of this study was to assess the effects of competitive and noncompetitive 5α-RIs on serum and intra-prostatic androgens in beagle dogs.Methods Twenty beagles with spontaneous benign prostatic hyperplasia were randomly allocated into two groups:epristeride group (n=10) in which beagles were treated with epristeride at 1 mg/kg once a day for 3 months,and finasteride group (n=10) in which beagles were treated with finasteride at 1 mg/kg once a day for 3 months.The levels of intra-prostatic testosterone and DHT were measured before treatment and on day one after three months medication.Serum levels of testosterone and DHT were measured at the same time points.Changes in androgen levels before and after treatment were analyzed,and comparisons were made within each treatment group and between treatment groups.Results After 3-month treatment,serum and intra-prostatic DHT levels all decreased significantly in both the epristeride and finasteride groups.The change of DHT in serum was significantly higher in the finasteride group (-14% and-43% in epristeride and finasteride groups respectively,with P<0.001); however there was no significant difference in the changes of intra-prostatic DHT between the two groups (-47% and-51% in epristeride and finasteride groups,respectively,P=0.304).The decreases in DHT levels were accompanied by reciprocal increases in serum and intra-prostatic testosterone levels.Changes of testosterone were significantly higher in finasteride group both in serum (20% and 42%in epristeride and finasteride groups,respectively,P<0.001) and in

  10. Prospective study of exercise intervention in prostate cancer patients on androgen deprivation therapy

    International Nuclear Information System (INIS)

    Androgen deprivation therapy (ADT) is an important component of modern prostate cancer treatment. Survival benefits from neo-adjuvant and adjuvant hormones may take years to manifest, and balancing this with potential morbidity of therapy can be challenging. This study aimed to assess whether education and short-term combined aerobic and resistance exercises could help to ameliorate the adverse side effects of ADT. Eight hundred fifty-nine patients with relapsed or metastatic prostate cancer on leuprorelin acetate were allocated to three interventional streams based on patient preference and medical fitness: supervised group (Face-to-Face) exercise sessions, home-based (At Home) exercise or a support programme for those incapable of exercising (Support). Patients enrolled onto Face to Face underwent measurement of body composition and cardiorespiratory fitness variables at baseline and programme completion. Patients in the exercise streams were surveyed to determine the programme's impact on physical fitness and well-being. Statistically significant improvements (p<0.001) were seen in all measured cardiorespiratory fitness and strength variables. Programme attrition rates were low (75/859; 8.7%), the primary reason for withdrawal being discontinuation of hormones (70%). Programme satisfaction was high, with 98% of surveyed patients reporting a positive impact on fitness and 97% planning to continue exercising after programme completion. At 6 months, improved physical and emotional well-being was reported by 93 and 79% of patients, respectively. A short-term structured exercise intervention results in high compliance and significant improvements in muscle strength and cardiorespiratory fitness in prostate cancer patients on ADT.

  11. Parameter estimation and optimal scheduling algorithm for a mathematical model of intermittent androgen suppression therapy for prostate cancer

    Science.gov (United States)

    Guo, Qian; Lu, Zhichang; Hirata, Yoshito; Aihara, Kazuyuki

    2013-12-01

    We propose an algorithm based on cross-entropy to determine parameters of a piecewise linear model, which describes intermittent androgen suppression therapy for prostate cancer. By comparing with clinical data, the parameter estimation for the switched system shows good fitting accuracy and efficiency. We further optimize switching time points for the piecewise linear model to obtain a feasible therapeutic schedule. The simulation results of therapeutic effect are superior to those of previous strategy.

  12. Intermittent versus continuous androgen deprivation for locally advanced, recurrent or metastatic prostate cancer: a systematic review and meta-analysis

    OpenAIRE

    Botrel, Tobias Engel Ayer; Clark, Otávio; dos Reis, Rodolfo Borges; Pompeo, Antônio Carlos Lima; Ferreira, Ubirajara; Sadi, Marcus Vinicius; Bretas, Francisco Flávio Horta

    2014-01-01

    Background Prostate cancer is the most common cancer in older men in the United States (USA) and Western Europe. Androgen deprivation (AD) constitutes, in most cases, the first-line of treatment for these cases. The negative impact of CAD in quality of life, secondary to the adverse events of sustained hormone deprivation, plus the costs of this therapy, motivated the intermittent treatment approach. The objective of this study is to to perform a systematic review and meta-analysis of all ran...

  13. Clamp ablation of the testes compared to bilateral orchiectomy as androgen deprivation therapy for advanced prostate cancer

    OpenAIRE

    AD Zarrabi; CF Heyns

    2011-01-01

    PURPOSE: Burdizzo clamp ablation of the testes (CAT) may provide an incisionless, cost-effective form of androgen deprivation therapy (ADT) in men with adenocarcinoma of the prostate (ACP) who find bilateral orchiectomy (BO) unacceptable or can not afford medical ADT. The aim of this study was to compare CAT with BO as primary ADT in men with ACP. MATERIALS AND METHODS: Written, informed consent was obtained from men with locally advanced or metastatic ACP. Patients were prospectively randomi...

  14. Conformal radiotherapy with intensity modulation, regional deep hyperthermia and total androgen suppression in patients with a high risk prostate tumor, operated or not. Preliminary results in 20 patients

    International Nuclear Information System (INIS)

    Purpose: to evaluate the feasibility and the toxicity of association of I.M.R.T., regional deep hyperthermia and complete androgenic elimination for the patients suffering of a high risk prostate tumor. Conclusion: According to our experience the association of pelvis I.M.R.T., a complement of prostate irradiation, a regional deep hyperthermia and complete androgenic elimination by analog is feasible. In comparison with the modest toxicity that we previously observed for patients treated by three dimensional conformal radiotherapy limited to the prostate associated to a regional deep hyperthermia and a complete androgenic elimination, the tolerance of the association of pelvic I.M.R.T.,regional deep hyperthermia and complete androgenic elimination turns out better. (N.C.)

  15. Androgen receptor mutations

    OpenAIRE

    Brinkmann, Albert; Jenster, Guido; Ris-Stalpers, Carolyn; Korput, J. A G M; Brüggenwirth, Hennie; Boehmer, A.L.; Trapman, Jan

    1995-01-01

    textabstractMale sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syn...

  16. Sequential Androgen Receptor Pathway Inhibitor in Prostate Cancer: Piling-Up The Benefits or a Case for Cross-Resistance?

    Directory of Open Access Journals (Sweden)

    Bertrand Tombal

    2014-11-01

    Full Text Available In the last 10 years, there has been accumulating evidence that, even in a low serum testosterone environment, the androgen receptor (AR remains the main driver of prostate cancer progression. This has led to the discovery and clinical development of new anti-androgens and androgen biosynthesis inhibitors. Enzalutamide and abiraterone acetate are the lead compounds of this new generation of agents, but multiple other agents are on their way. Because they both target the ligand-dependent regulation of AR activity, it is plausible that cross-resistance may exist when both drugs are used sequentially, and that the benefit of these agents may fade away when sequencing them. As the exact mechanisms for cross- resistance between AR-targeted agents remain unclear at this point, additional clinical studies are crucial to define the exact combination or sequencing order that could yield highest clinical benefits. Moreover, new molecular targets are needed in order to address these resistances, as well as establishing biomarkers to improve patient selection that could most benefit from AR-targeted therapies, but also help develop novel agents to improve and optimise the management of castration-resistant prostate cancer and metastatic, castration-resistant prostate cancer.

  17. The prostate after administration of anabolic androgenic steroids: a morphometrical study in rats

    Directory of Open Access Journals (Sweden)

    Rafael Areas Vargas

    2013-09-01

    Full Text Available Purpose Many adverse effects have been associated with abuse of anabolic-androgenic steroids (AAS, including disorders of the urogenital tract. The objective of this study is to analyze the morphological modifications in the prostate ventral lobe of pubertal and adult rats chronically treated with AAS, using morphometric methods. Materials and Methods: We studied 39 male Wistar rats weighing between 400 g and 550 g. The rats were divided into four groups: (a control rats, with 105 days of age (C105 (n = 7; (b control rats with 65 days of age (C65 (n = 9, injected only with the vehicle (peanut oil; (c treated rats, with 105 days of age (T105 (n = 10 and (d treated rats with 65 days of age (T65 (n = 13. The treated rats were injected with nandrolone decanoate at a dose of 10 mg.Kg-1 body weight. The steroid hormone and the vehicle were administered by intramuscular injection once a week for eight weeks. The rats were killed at 161 days of age (C105 and T105 and 121 days of age (C65 and T65 and the ventral prostate lobe was dissected and processed for histology. The height of the acinar epithelium, the surface densities of the lumen, epithelium and stroma were observed with X400 magnification using an Olympus light microscope coupled to a Sony CCD video camera, and the images transferred to a Sony monitor KX14-CP1. The selected histological areas were then quantified using the M42 test-grid system on the digitized fields. The data were analyzed with the Graphpad software. To compare the quantitative data in both groups (controls and treated and the outcomes, Student's t-test was used (p < 0.05 was considered significant. Results: The weight (p < 0.001 and volume (p = 0.004 of the prostate ventral lobe showed differences between C65 and T65 groups and between C105 and T105 groups. The epithelium height showed no difference between groups C65 and T65 (p = 0.8509, but the T105 group showed an increase of 32% compared to C105 (p = 0.0089. Concerning

  18. Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression

    International Nuclear Information System (INIS)

    Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy

  19. Inhibitory effect of oridonin on androgen independent prostate cancer xenografts in nude mice%冬凌草甲素对雄激素非依赖性前列腺癌裸鼠移植瘤的抑制作用

    Institute of Scientific and Technical Information of China (English)

    徐凯; 郭剑明; 刘宇军; 徐志兵; 王国民

    2012-01-01

    Objective To research the inhibition effect of oridonin on androgen independent prostate cancer (AlPCa) xenografts in nude mice and its mechanism. Methods DU145 cells were injected subcutaneously to 20 male BALB/c-nude mice and those mice were randomly divided into oridonin group and control group. From day 2 after the injection, the mice were fed with 0.9% saline solution in the control group and odidonin (15 mg·Kg-1·D-1) in the oridonin group every day. The average size of xenografts was measured every week from week 2 to week 7. At the end of week 7, all mice were executed and the tumors were removed. The Mrna expression of G1/S regulatory factor p 16, cell proliferation related factor interleukin (IL-6 and immune escape related factor indoleamine 2, 3-dioxygenase (IDO) were analyzed by reverse transcriptase polymerase chain reaction. Results The growth of xenografts in the oridonin group was significantly inhibited, and the tumors were significantly smaller than those in the control group from the end of week 3 to week 7 (all P<0.001). Compared with control group, the growth inhibiting rate of the tumors in the oridonin group was 58.12% at the end of week 7. After 7 weeks, the average level of p16 Mrna in the control group was lower than that in the oridonin group (0.46 vs. 0.95); the average level of IL-6 Mrna in the control group was high than that in the oridonin group (0.33 vs. 0.02); the average level of IDO Mrna in the control group was 0.08, but it could not be measured in the oridonin group because there were no obvious electrophoretic bands. Conclusion Oridonin can obviously inhibit the growth of DU145 cells, indicating that oridonin has the antitumor activity to AlPCa. It may be achieved by downregulating cell cycle, immune escape and IL-6 level.%目的 探讨冬凌草甲素对雄激素非依赖性前列腺癌(AIPCa)裸鼠移植瘤的抑制作用及其机制.方法 雄性裸小鼠20只,皮下接种DU145细胞,随机分成用药组和

  20. External Beam Radiation Therapy and Abiraterone in Men With Localized Prostate Cancer: Safety and Effect on Tissue Androgens

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Eunpi [University of Washington School of Medicine, Seattle, Washington (United States); Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Mostaghel, Elahe A. [Fred Hutchinson Cancer Research Center, Seattle, Washington (United States); Russell, Kenneth J.; Liao, Jay J.; Konodi, Mark A. [University of Washington School of Medicine, Seattle, Washington (United States); Kurland, Brenda F. [University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Marck, Brett T. [Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Matsumoto, Alvin M. [University of Washington School of Medicine, Seattle, Washington (United States); Veterans Affairs Puget Sound Health Care System, Seattle, Washington (United States); Dalkin, Bruce L. [University of Washington School of Medicine, Seattle, Washington (United States); Montgomery, R. Bruce, E-mail: rbmontgo@uw.edu [University of Washington School of Medicine, Seattle, Washington (United States)

    2015-06-01

    Purpose: Optimizing androgen suppression may provide better control of localized prostate cancer (PCa). Numerous trials have supported the benefit of combining androgen deprivation therapy with definitive radiation therapy in men with locally advanced or high-grade disease. Addition of abiraterone to luteinizing hormone-releasing hormone agonist (LHRHa) with radiation has not been reported. We examined the safety of this combination as well as its impact on androgen suppression. Methods and Materials: A prospective, phase 2 study was conducted in men with localized PCa treated with 6 months of neoadjuvant and concurrent abiraterone with LHRHa and radiation. Duration of adjuvant LHRHa was at the discretion of the treating clinician. Prostate biopsy assays were obtained prior to the start of therapy and prior to radiation. Sera and tissue androgen levels were measured by liquid chromatography-tandem mass spectrometry. Results: A total of 22 men with intermediate- (n=3) and high-risk PCa (n=19) received study therapy. Sixteen men completed the intended course of abiraterone, and 19 men completed planned radiation to 77.4 to 81 Gy. Radiation to pelvic nodes was administered in 20 men. The following grade 3 toxicities were reported: lymphopenia (14 patients), fatigue (1 patient), transaminitis (2 patients), hypertension (2 patients), and hypokalemia (1 patient). There were no grade 4 toxicities. All 21 men who complied with at least 3 months of abiraterone therapy had a preradiation prostate-specific antigen (PSA) concentration nadir of <0.3 ng/mL. Median levels of tissue androgen downstream of CYP17A were significantly suppressed after treatment with abiraterone, and upstream steroids were increased. At median follow-up of 21 months (range: 3-37 months), only 1 patient (who had discontinued abiraterone at 3 months) had biochemical relapse. Conclusions: Addition of abiraterone to LHRHa with radiation is safe and achieves effective prostatic androgen suppression

  1. Effects of 2,4-D and DCP on the DHT-induced androgenic action in human prostate cancer cells.

    Science.gov (United States)

    Kim, Hyun-Jung; Park, Young In; Dong, Mi-Sook

    2005-11-01

    2,4-Dichlorophenoxyacetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (DCP) are used extensively in agriculture as herbicides, and are suspected of potential endocrine disruptor activity. In a previous study, we showed that these compounds exhibited synergistic androgenic effects by co-treatment with testosterone in the Hershberger assay. To elucidate the mechanisms of the synergistic effects of these compounds on the androgenicity of testosterone, the androgenic action of 2,4-D and DCP was characterized using a mammalian detection system in prostate cancer cell lines. In in vitro assay systems, while 2,4-D or DCP alone did not show androgenic activity, 2,4-D or DCP with 5alpha-dihydroxytestosterone (DHT) exhibited synergistic androgenic activities. Co-treatment of 10 nM 2,4-D or DCP with 10 nM DHT was shown to stimulate the cell proliferation by 1.6-fold, compared to 10 nM DHT alone. In addition, in transient transfection assays, androgen-induced transactivation was also increased to a maximum of 32-fold or 1.28-fold by co-treatment of 2,4-D or DCP with DHT, respectively. However, 2,4-D and DCP exerted no effects on either mRNA or protein levels of AR. In a competitive AR binding assay, 2,4-D and DCP inhibited androgen binding to AR, up to 50% at concentrations of approximately 0.5 microM for both compounds. The nuclear translocation of green fluorescent protein-AR fusion protein in the presence of DHT was promoted as the result of the addition of 2,4-D and DCP. Collectively, these results that 2,4-D and DCP enhanced DHT-induced AR transcriptional activity might be attributable, at least in part, to the promotion of AR nuclear translocation.

  2. p21-Activated kinase 6 (PAK6) inhibits prostate cancer growth via phosphorylation of androgen receptor and tumorigenic E3 ligase murine double minute-2 (Mdm2).

    Science.gov (United States)

    Liu, Tong; Li, Yang; Gu, Hui; Zhu, Ge; Li, Jiabin; Cao, Liu; Li, Feng

    2013-02-01

    The androgen receptor (AR) signaling pathway plays a crucial role in the development and growth of prostate malignancies. Regulation of AR homeostasis in prostate tumorigenesis has not yet been fully characterized. In this study, we demonstrate that p21-activated kinase 6 (PAK6) inhibits prostate tumorigenesis by regulating AR homeostasis. First, we demonstrated that in normal prostate epithelium, AR co-localizes with PAK6 in the cytoplasm and translocates into the nucleus in malignant prostate. Furthermore, AR phosphorylation at Ser-578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon androgen stimuli. We also showed that PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. Moreover, we found that Thr-158 collaborates with Ser-186 for AR-Mdm2 association and AR ubiquitin-mediated degradation as it facilitates PAK6-mediated AR homeostasis. PAK6 knockdown promotes prostate tumor growth in vivo. Interestingly, we found a strong inverse correlation between PAK6 and AR expression in the cytoplasm of prostate cancer cells. These observations indicate that PAK6 may be important for the maintenance of androgen-induced AR signaling homeostasis and in prostate malignancy, as well as being a possible new therapeutic target for AR-positive and hormone-sensitive prostate cancer.

  3. Corepressor effect on androgen receptor activity varies with the length of the CAG encoded polyglutamine repeat and is dependent on receptor/corepressor ratio in prostate cancer cells.

    Science.gov (United States)

    Buchanan, Grant; Need, Eleanor F; Barrett, Jeffrey M; Bianco-Miotto, Tina; Thompson, Vanessa C; Butler, Lisa M; Marshall, Villis R; Tilley, Wayne D; Coetzee, Gerhard A

    2011-08-01

    The response of prostate cells to androgens reflects a combination of androgen receptor (AR) transactivation and transrepression, but how these two processes differ mechanistically and influence prostate cancer risk and disease outcome remain elusive. Given recent interest in targeting AR transrepressive processes, a better understanding of AR/corepressor interaction and responses is warranted. Here, we used transactivation and interaction assays with wild-type and mutant ARs, and deletion AR fragments, to dissect the relationship between AR and the corepressor, silencing mediator for retinoic acid and thyroid hormone receptors (SMRT). We additionally tested how these processes are influenced by AR agonist and antagonist ligands, as well as by variation in the polyglutamine tract in the AR amino terminal domain (NTD), which is encoded by a polymorphic CAG repeat in the gene. SMRT was recruited to the AR ligand binding domain by agonist ligand, and as determined by the effect of strategic mutations in activation function 2 (AF-2), requires a precise conformation of that domain. A distinct region of SMRT also mediated interaction with the AR-NTD via the transactivation unit 5 (TAU5; residues 315-538) region. The degree to which SMRT was able to repress AR increased from 17% to 56% as the AR polyglutamine repeat length was increased from 9 to 42 residues, but critically this effect could be abolished by increasing the SMRT:AR molar ratio. These data suggest that the extent to which the CAG encoded polyglutamine repeat influences AR activity represents a balance between corepressor and coactivator occupancy of the same ligand-dependent and independent AR interaction surfaces. Changes in the homeostatic relationship of AR to these molecules, including SMRT, may explain the variable penetrance of the CAG repeat and the loss of AR signaling flexibility in prostate cancer progression.

  4. Prostate cancer and metastasis initiating stem cells

    Institute of Scientific and Technical Information of China (English)

    Kathleen Kelly; Juan Juan Yin

    2008-01-01

    Androgen refractory prostate cancer metastasis is a major clinical challenge.Mechanism-based approaches to treating prostate cancer metastasis require an understanding of the developmental origin of the metastasis-initiating cell.Properties of prostate cancer metastases such as plasticity with respect to differentiated phenotype and androgen independence are consistent with the transformation of a prostate epithelial progenitor or stem cell leading to metastasis.This review focuses upon current evidence and concepts addressing the identification and properties of normal prostate stem or progenitor cells and their transformed counterparts.

  5. Combination of genistein with ionizing radiation on andro-gen-independent prostate cancer cells

    Institute of Scientific and Technical Information of China (English)

    Sen-XiangYan; YasuoEjima; RyoheiSasaki; Shu-SenZheng; YusukeDemizu; ToshinoriSoejima; KazuroSugimura

    2004-01-01

    Aim: To study the effect of the combined use of genistein and ionizing radiation (IR) on prostate DUI45 cancer cells. Methods: DU145, an androgen-independent human prostate cancer cell line, was used in the experiment.Clonogenic assay was used to compare the survival of DU145 cells after treatments with genistein alone and in combination with graded IR. Apoptosis was assayed by DNA ladder and TUNEL stain. Cell cycle alterations were observed by flow cytometry and related protein expressions by immunoblotting. Results: Clonogenic assay demonstrated that genistein, even at low to medium concentrations, enhanced the radiosensitivity of DU 145 cells. Twenty four hours after treatment with IR and/or genistein, apoptosis was mainly seen with genistein at high concentrations and was minimally related to IR. At 72 h, apoptosis also occurred in treatment with lower concentration of genistein,especially when combined with IR. While both IR and genistein led to G2/M cell cycle arrest, combination of them further increased the DUI45 cells at G2/M phase. This G2/M arrest was largely maintained at 72 h, accompanied by increasing apoptosis and hyperdiploid cell population. Cell-cycle related protein analysis disclosed biphasic changes in cyclin B 1 and less dramatically cdc-2, but stably elevated p21cip1 levels with increasing genistein concentrations.Conclusion: Genistein enhanced the radiosensitivity of DUI45 prostate cancer cells. The mechanisms might be involved in the increased apoptosis, prolonged cell cycle arrest and impaired damage repair. (Asian J Androl 2004 Dec; 6: 285-290)

  6. Systemic therapy for the treatment of hormone-sensitive metastatic prostate cancer: from intermittent androgen deprivation therapy to chemotherapy.

    Science.gov (United States)

    Liaw, Bobby C; Shevach, Jeffrey; Oh, William K

    2015-03-01

    Treatment of advanced prostate cancer has changed considerably in recent years, but the vast majority of advances have been made in patients with metastatic castration-resistant disease. There have been relatively fewer advances in the earlier, hormonally responsive stage of metastatic disease. Since the empiric establishment of androgen deprivation therapy as first-line therapy for metastatic prostate cancer decades ago, there have been multiple studies looking at variations of suppressing testosterone, but the overall paradigm has not been strongly challenged until more recently. In particular, the dramatic results reported by the CHAARTED trial not only bring chemotherapy to an arena historically dominated solely by hormonal therapy but also stimulate renewed efforts into improving upon our management of metastatic hormone-sensitive prostate cancer. PMID:25677235

  7. Human α(2)β(1)(HI) CD133(+VE) epithelial prostate stem cells express low levels of active androgen receptor.

    Science.gov (United States)

    Williamson, Stuart C; Hepburn, Anastasia C; Wilson, Laura; Coffey, Kelly; Ryan-Munden, Claudia A; Pal, Deepali; Leung, Hing Y; Robson, Craig N; Heer, Rakesh

    2012-01-01

    Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α(2)β(1)(HI) CD133(+VE)), transiently amplifying (α(2)β(1)(HI) CD133(-VE)) and terminally differentiated (α(2)β(1)(LOW) CD133(-VE)) cells. AR transcript and protein expression was confirmed in α(2)β(1)(HI) CD133(+VE) and CD133(-VE) progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α(2)β(1)(HI) CD133(+VE) stem cells and 68% (±12%) in α(2)β(1)(HI) CD133(-VE) transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α(2)β(1)(HI) CD133(+VE) stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133(+VE) cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis.

  8. Morphology of the epithelial cells and expression of androgen receptor in rat prostate dorsal lobe in experimental hyperprolactinemia.

    Directory of Open Access Journals (Sweden)

    Marcin Wylot

    2006-04-01

    Full Text Available The effect of hyperprolactinemia on the prostate has not been well investigated. Since androgens play an important role in prostate development, growth and function, the goal of the present study was to estimate the influence of hyperprolactinemia on expression of the androgen receptor (AR in rat epithelial cells of prostate dorsal lobe and on morphology of these cells. Studies were performed on sexually mature male Wistar rats. The experimental group rats received metoclopramide (MCP intraperitoneally to provoke hyperprolactinemia. The control group animals were given saline in the same way. For light and electron microscopy the prostate dorsal lobes were obtained routinely. To evaluate the intensity of immunohistochemical reaction for AR in epithelial cells, the optical density was measured and computer-assisted image analysis system was used. Morphological observations of the dorsal lobe epithelial cells were carried out in transmission electron microscope. MCP caused over twofold increase in prolactin (PRL serum levels. In rats with hyperprolactinemia, the testosterone levels (T were twofold decreased. The intensity of immunohistochemical reaction for AR in epithelial cells of dorsal lobe in the experimental group was significantly lower than in the control group. In the dorsal lobe epithelial cells of experimental group animals, the transmission electron microscopy (TEM revealed highly dilated RER cisternae and reduced number of microvilli on the cellular surface when compared to the control group. The results show that hyperprolactinemia in male rats causes morphological abnormalities in the dorsal lobe of prostate. The abnormalities are caused by elevated prolactin either directly or indirectly through decreased level of testosterone. Decreased expression of AR in epithelial cells of prostate dorsal lobe is likely to be caused by decreased testosterone level.

  9. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Gunnarsson, Orvar, E-mail: orvar.gunnarsson@uphs.upenn.edu [Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, 3400 Spruce Street, 16 Penn Tower, Philadelphia, PA 19104 (United States); Basaria, Shehzad [Department of Medicine, Section of Men’s Health, Aging and Metabolism, Brigham and Women’s Hospital, Boston, MA 02115 (United States); Gignac, Gretchen A. [Department of Medicine, Section of Hematology and Oncology, Boston University School of Medicine, Boston, MA 02118 (United States)

    2015-04-22

    Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

  10. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

    Directory of Open Access Journals (Sweden)

    Orvar Gunnarsson

    2015-04-01

    Full Text Available Background: Androgen deprivation therapy (ADT for prostate cancer (PCa is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI, vitamin-D status, bone mineral density (BMD, dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4% patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications.

  11. Metabolic syndrome in patients with prostate cancer undergoing intermittent androgen-deprivation therapy

    Science.gov (United States)

    Rezaei, Mohammadali Mohammadzadeh; Rezaei, Mohammadhadi Mohammadzadeh; Ghoreifi, Alireza; Kerigh, Behzad Feyzzadeh

    2016-01-01

    Introduction: The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. Methods: In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. Results: Mean age of the patients was 67.5 ± 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their six- and 12-month followups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. Conclusions: Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa.

  12. Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer

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    Lior Z. Braunstein

    2014-01-01

    Full Text Available Background. Increasing body mass index (BMI is associated with increased risk of mortality; however, quantifying weight gain in men undergoing androgen deprivation therapy (ADT for prostate cancer (PC remains unexplored. Methods. Between 1995 and 2001, 206 men were enrolled in a randomized trial evaluating the survival difference of adding 6 months of ADT to radiation therapy (RT. BMI measurements were available in 171 men comprising the study cohort. The primary endpoint was weight gain of ≥10 lbs by 6-month followup. Logistic regression analysis was performed to assess whether baseline BMI or treatment received was associated with this endpoint adjusting for known prognostic factors. Results. By the 6-month followup, 12 men gained ≥10 lbs, of which 10 (83% received RT + ADT and, of these, 7 (70% were obese at randomization. Men treated with RT as compared to RT + ADT were less likely to gain ≥10 lbs (adjusted odds ratio (AOR: 0.18 [95% CI: 0.04–0.89]; P=0.04, whereas this risk increased with increasing BMI (AOR: 1.15 [95% CI: 1.01–1.31]; P=0.04. Conclusions. Consideration should be given to avoid ADT in obese men with low- or favorable-intermediate risk PC where improved cancer control has not been observed, but shortened life expectancy from weight gain is expected.

  13. Psychological effects of androgen-deprivation therapy on men with prostate cancer and their partners.

    Science.gov (United States)

    Donovan, Kristine A; Walker, Lauren M; Wassersug, Richard J; Thompson, Lora M A; Robinson, John W

    2015-12-15

    The clinical benefits of androgen-deprivation therapy (ADT) for men with prostate cancer (PC) have been well documented and include living free from the symptoms of metastases for longer periods and improved quality of life. However, ADT comes with a host of its own serious side effects. There is considerable evidence of the adverse cardiovascular, metabolic, and musculoskeletal effects of ADT. Far less has been written about the psychological effects of ADT. This review highlights several adverse psychological effects of ADT. The authors provide evidence for the effect of ADT on men's sexual function, their partner, and their sexual relationship. Evidence of increased emotional lability and depressed mood in men who receive ADT is also presented, and the risk of depression in the patient's partner is discussed. The evidence for adverse cognitive effects with ADT is still emerging but suggests that ADT is associated with impairment in multiple cognitive domains. Finally, the available literature is reviewed on interventions to mitigate the psychological effects of ADT. Across the array of adverse effects, physical exercise appears to have the greatest potential to address the psychological effects of ADT both in men who are receiving ADT and in their partners. PMID:26372364

  14. Cardiometabolic and Skeletal Risk Factors in Black Men with Prostate Cancer Starting Androgen Deprivation Therapy

    International Nuclear Information System (INIS)

    Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with multiple metabolic complications, previously predominantly evaluated in the white population. Methods: A chart-based retrospective review was conducted on black patients with PCa, considered for ADT, from September 2007 to July 2010. Baseline data were collected on body mass index (BMI), vitamin-D status, bone mineral density (BMD), dyslipidemia and diabetes. Overweight and obesity were classified as BMI ≥ 25 and BMI ≥ 30, respectively. Vitamin-D sufficiency was defined as levels ≥30 ng/mL, insufficiency as <30 ng/mL and deficiency as ≤20 ng/mL. Osteopenia was defined as T scores between −1 to −2.5 and osteoporosis when T scores ≤−2.5. Results: Of the initial cohort of 130 black men, 111 (85.4%) patients underwent ADT. At baseline, average BMI was 28.1 ± 5.9 with 43.3% of men being overweight and 30.8% obese. More than one-third of the patients had pre-existing dyslipidemia while 28.8% were diabetics. 50% were vitamin-D deficient while 41% had low bone mass. Conclusions: Black men with PCa presenting for consideration of ADT have a high prevalence of existing metabolic risk factors. Close monitoring of this patient population is needed during ADT to prevent and treat metabolic complications

  15. Longitudinal Magnetic Resonance Imaging-Based Assessment of Vascular Changes and Radiation Response in Androgen-Sensitive Prostate Carcinoma Xenografts under Androgen-Exposed and Androgen-Deprived Conditions

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    Kathrine Røe

    2010-10-01

    Full Text Available Prostate cancer (PCa patients receive androgen-deprivation therapy (ADT to reduce tumor burden. However, complete eradication of PCa is unusual, and recurrent disease is evident within approximately 2 years in high-risk patients. Clinical evidence suggests that combining ADT with radiotherapy improves local control and disease-free survival in these patients compared with radiotherapy alone. We investigated whether vascularization of androgen-sensitive PCa xenografts changed after ADT and whether such therapy affected radiation response. CWR22 xenografts received combinations of ADT by castration (CWR22-cas and 15 Gy of single-dose irradiation. At a shortest tumor diameter of 8 mm, vascularization was visualized by dynamic contrast-enhanced magnetic resonance imaging before radiation and 1 and 9 days after radiation. Voxel-wise quantitative modeling of contrast enhancement curves extracted the hemodynamic parameter Ktrans, reflecting a combination of permeability, density, and blood flow. Tumor volumes and prostate-specific antigen (PSA were monitored during the experiment. The results showed that Ktrans of CWR22-cas tumors 36±4 days after ADT was 47.1% higher than Ktrans of CWR22 tumors (P = .01. CWR22-cas tumors showed no significant changes in Ktrans after radiation, whereas Ktrans of CWR22 tumors at day 1 decreased compared with pretreatment values (P = .04 before a continuous increase from day 1 to day 9 followed (P = .01. Total PSA in blood correlated positively to tumor volume (r = 0.59, P < .01. In conclusion, androgen-exposed xenografts demonstrated radiation-induced reductions in vascularization and tumor volumes, whereas androgen-deprived xenografts showed increased vascularization and growth inhibition, but no significant additive effect of radiation.

  16. Androgen Receptor-Mediated Growth Suppression of HPr-1AR and PC3-Lenti-AR Prostate Epithelial Cells.

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    Young-Chae Kim

    Full Text Available The androgen receptor (AR mediates the developmental, physiologic, and pathologic effects of androgens including 5α-dihydrotestosterone (DHT. However, the mechanisms whereby AR regulates growth suppression and differentiation of luminal epithelial cells in the prostate gland and proliferation of malignant versions of these cells are not well understood, though they are central to prostate development, homeostasis, and neoplasia. Here, we identify androgen-responsive genes that restrain cell cycle progression and proliferation of human prostate epithelial cell lines (HPr-1AR and PC3-Lenti-AR, and we investigate the mechanisms through which AR regulates their expression. DHT inhibited proliferation of HPr-1AR and PC3-Lenti-AR, and cell cycle analysis revealed a prolonged G1 interval. In the cell cycle, the G1/S-phase transition is initiated by the activity of cyclin D and cyclin-dependent kinase (CDK complexes, which relieve growth suppression. In HPr-1AR, cyclin D1/2 and CDK4/6 mRNAs were androgen-repressed, whereas CDK inhibitor, CDKN1A, mRNA was androgen-induced. The regulation of these transcripts was AR-dependent, and involved multiple mechanisms. Similar AR-mediated down-regulation of CDK4/6 mRNAs and up-regulation of CDKN1A mRNA occurred in PC3-Lenti-AR. Further, CDK4/6 overexpression suppressed DHT-inhibited cell cycle progression and proliferation of HPr-1AR and PC3-Lenti-AR, whereas CDKN1A overexpression induced cell cycle arrest. We therefore propose that AR-mediated growth suppression of HPr-1AR involves cyclin D1 mRNA decay, transcriptional repression of cyclin D2 and CDK4/6, and transcriptional activation of CDKN1A, which serve to decrease CDK4/6 activity. AR-mediated inhibition of PC3-Lenti-AR proliferation occurs through a similar mechanism, albeit without down-regulation of cyclin D. Our findings provide insight into AR-mediated regulation of prostate epithelial cell proliferation.

  17. Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies.

    Science.gov (United States)

    Moilanen, Anu-Maarit; Riikonen, Reetta; Oksala, Riikka; Ravanti, Laura; Aho, Eija; Wohlfahrt, Gerd; Nykänen, Pirjo S; Törmäkangas, Olli P; Palvimo, Jorma J; Kallio, Pekka J

    2015-07-03

    Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

  18. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance

    Institute of Scientific and Technical Information of China (English)

    Merritt P Edlind; Andrew C Hsieh

    2014-01-01

    Prostate cancer (PCa) is the second most common malignancy among men in the world. Castration-resistant prostate cancer (CRPC) is the lethal form of the disease, which develops upon resistance to ifrst line androgen deprivation therapy (ADT). Emerging evidence demonstrates a key role for the PI3K-AKT-mTOR signaling axis in the development and maintenance of CRPC. This pathway, which is deregulated in the majority of advanced PCas, serves as a critical nexus for the integration of growth signals with downstream cellular processes such as protein synthesis, proliferation, survival, metabolism and differentiation, thus providing mechanisms for cancer cells to overcome the stress associated with androgen deprivation. Furthermore, preclinical studies have elucidated a direct connection between the PI3K-AKT-mTOR and androgen receptor (AR) signaling axes, revealing a dynamic interplay between these pathways during the development of ADT resistance. Thus, there is a clear rationale for the continued clinical development of a number of novel inhibitors of the PI3K pathway, which offer the potential of blocking CRPC growth and survival. In this review, we will explore the relevance of the PI3K-AKT-mTOR pathway in PCa progression and castration resistance in order to inform the clinical development of speciifc pathway inhibitors in advanced PCa. In addition, we will highlight current deifciencies in our clinical knowledge, most notably the need for biomarkers that can accurately predict for response to PI3K pathway inhibitors.

  19. [7α-18F]fluoro-17α-methyl-5α-dihydrotestosterone: a ligand for androgen receptor-mediated imaging of prostate cancer

    International Nuclear Information System (INIS)

    We have synthesized a 18F-labeled androgen, [7α-18F]fluoro-17α-methyl-5α-dihydrotestosterone, in a no-carrier-added radiosynthesis by exchange of 18F- (tetrabutylammonium fluoride) with the 7β-tosyloxy of 17α-methyl-5α-dihydrotestosterone. The nonradioactive steroid binds with high affinity and specificity to the androgen receptor and binds poorly, if at all, to other steroid receptors and plasma sex hormone binding globulin. The 7α-18F-androgen concentrates markedly in the prostate of rats by an androgen receptor-dependent mechanism. It is likely that [7α-18F]fluoro-17α-methyl-5α-dihydrotestosterone will be an excellent positron emission tomography imaging agent for prostate cancer

  20. Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene

    OpenAIRE

    Schayek, Hagit; Bentov, Itay; Sun, Shihua; Plymate, Stephen R; Werner, Haim

    2010-01-01

    The progression of prostate cancer from an organ-confined, androgen-sensitive disease to a metastatic one is associated with dysregulation of androgen receptor (AR)-regulated target genes and with a decrease in insulin-like growth factor-I receptor (IGF1R) expression. DNA methylation of CpG islands is an epigenetic mechanism associated with gene silencing. Recent studies have demonstrated that methylation occurs early in prostate carcinogenesis and, furthermore, may contribute to androgen ind...

  1. Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy.

    Science.gov (United States)

    O'Neill, Daniel; Jones, Dominic; Wade, Mark; Grey, James; Nakjang, Sirintra; Guo, Wenrui; Cork, David; Davies, Barry R; Wedge, Steve R; Robson, Craig N; Gaughan, Luke

    2015-09-22

    The persistence of androgen receptor (AR) signalling in castrate-resistant prostate cancer (CRPC) highlights the unmet clinical need for the development of more effective AR targeting therapies. A key mechanism of therapy-resistance is by selection of AR mutations that convert anti-androgens to agonists enabling the retention of androgenic signalling in CRPC. To improve our understanding of these receptors in advanced disease we developed a physiologically-relevant model to analyse the global functionality of AR mutants in CRPC. Using the bicalutamide-activated AR(W741L/C) mutation as proof of concept, we demonstrate that this mutant confers an androgenic-like signalling programme and growth promoting phenotype in the presence of bicalutamide. Transcriptomic profiling of AR(W741L) highlighted key genes markedly up-regulated by the mutant receptor, including TIPARP, RASD1 and SGK1. Importantly, SGK1 expression was found to be highly expressed in the KUCaP xenograft model and a CRPC patient biopsy sample both of which express the bicalutamide-activated receptor mutant. Using an SGK1 inhibitor, AR(W741L) transcriptional and growth promoting activity was reduced indicating that exploiting functional distinctions between receptor isoforms in our model may provide new and effective therapies for CRPC patients.

  2. The Expression of the Androgen Receptor and Estrogen Receptor 1 is Related to Sex Dimorphism in the Gerbil Prostate Development.

    Science.gov (United States)

    Sanches, Bruno D A; Maldarine, Juliana S; Zani, Bruno C; Biancardi, Manoel F; Santos, Fernanda C A; Góes, Rejane M; Vilamaior, Patricia S L; Taboga, Sebastião R

    2016-08-01

    The development of the prostate gland in females has not yet been clearly elucidated, and the sexual dimorphism associated with such gland development in general is far from being understood. In the present study, we used tridimensional (3D) reconstructions and histochemical and immunohistochemical techniques to describe the sexual dimorphism and its causes in the early postnatal development of the prostate in male and female Mongolian gerbils (Meriones unguiculatus). We observed that the female prostate was smaller, had fewer branches throughout the development, and underwent differentiation earlier than that in males. Also, the expression of the estrogen receptor 1 (ESR1 or ER-alpha) and fibroblast growth factor 10 (FGF10) was decreased in the periductal region, and the expression of the androgen receptor (AR) was increased in the epithelium. All together, these changes decreased proliferation and branching and led to an earlier prematuration of the female prostate. These new data shed light on the underlying mechanisms involved with the sexual dimorphism in the development of the prostate. Anat Rec, 299:1130-1139, 2016. © 2016 Wiley Periodicals, Inc. PMID:27184581

  3. Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

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    Lee C

    2012-07-01

    Full Text Available Abstract Background Prostate cancer is the most commonly diagnosed non-melanoma cancer among men. Androgen deprivation therapy (ADT has been the core therapy for men with advanced prostate cancer. It is only in recent years that clinicians began to recognize the cognitive-psychosocial side effects from ADT, which significantly compromise the quality of life of prostate cancer survivors. The objectives of the study are to determine the efficacy of a simple and accessible home-based, walking exercise program in promoting cognitive and psychosocial functions of men with prostate cancer receiving ADT. Methods A 6-month prospective, single-blinded, randomized controlled trial will be conducted to compare the Exercise Group with the Control Group. Twenty men with prostate cancer starting ADT will be recruited and randomly assigned to one of the two groups: the Exercise Group will receive instructions in setting up an individualized 6-month home-based, walking exercise program, while the Control Group will receive standard medical advice from the attending physician. The primary outcomes will be psychosocial and cognitive functions. Cognitive functions including memory, attention, working memory, and executive function will be assessed using a battery of neurocognitive tests at baseline and 6 months. Psychosocial functions including depression, anxiety and self-esteem will be assessed at baseline, 3 and 6 months using the Center for Epidemiological Studies Depression Scale, Spielberger State-Trait Anxiety Inventory, and Rosenberg Self-Esteem Scale. Discussion The significance of the cognitive-psychosocial side effects of ADT in men with prostate cancer has only been recently recognized, and the management remains unclear. This study addresses this issue by designing a simple and accessible home-based, exercise program that may potentially have significant impact on reducing the cognitive and psychosocial side effects of ADT, and ultimately

  4. Positive association of the androgen receptor CAG repeat length polymorphism with the risk of prostate cancer.

    Science.gov (United States)

    Paz-Y-Miño, César; Robles, Paulo; Salazar, Carolina; Leone, Paola E; García-Cárdenas, Jennyfer M; Naranjo, Manuel; López-Cortés, Andrés

    2016-08-01

    Prostate cancer (PC) is the most frequently diagnosed cancer in Ecuador (15.6%). The androgen receptor gene codes for a protein that has an androgen‑binding domain, DNA‑binding domain and N‑terminal domain, which contains two polymorphic trinucleotide repeats (CAG and GGC). The aim of the present study was to determine whether variations in the number of repetitions of CAG and GGC are associated with the pathological features and the risk of developing PC. The polymorphic CAG and GGC repeat lengths in 108 mestizo patients with PC, 148 healthy mestizo individuals, and 78 healthy indigenous individuals were examined via a retrospective case‑control study. Genotypes were determined by genomic sequencing. The results demonstrated that patients with ≤21 CAG repeats have an increased risk of developing PC [odds ratio (OR)=2.99, 95% confidence interval (CI) =1.79‑5.01; P<0.001]. The presence of ≤21 CAG repeats was also associated with a tumor stage ≥T2c (OR=4.75; 95% CI=1.77‑12.72; P<0.005) and a Gleason score ≥7 (OR=2.9; 95% CI=1.1‑7.66; P=0.03). In addition, the combination of ≤21 CAG and ≥17 GGC repeats was associated with the risk of developing PC (OR=2.42; 95% CI=1.38‑4.25; P=0.002) and with tumor stage ≥T2c (OR=2.77; 95% CI=1.13‑6.79; P=0.02). In conclusion, the histopathological characteristics and PC risk in Ecuadorian indigenous and mestizo populations differs in association with the CAG repeats, and the combination of CAG and GGC repeats. PMID:27357524

  5. IκB Kinases Modulate the Activity of the Androgen Receptor in Prostate Carcinoma Cell Lines

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    Garima Jain

    2012-03-01

    Full Text Available Enhanced nuclear localization of nuclear factor κB (NF-κB in prostate cancer (PCa samples and constitutive NF-κB signaling in a class of PCa cell lines with low androgen receptor (AR expression (PC3 and DU-145 imply an important role of the IκB kinase (IKK/NF-κB system in PCa. However, most PCa and PCa cell lines depend on the activity of the AR, and the role of NF-κB in these AR-expressing PCa remains unclear. Here, we demonstrate that inhibition of NF-κB signaling by the IKK inhibitor BMS345541 reduced proliferation and increased apoptosis in AR-expressing PCa cell lines. Furthermore, AR activity and target gene expression were distinctively reduced, whereas AR protein levels remained unaltered on BMS345541 treatment. Similar effects were observed particularly after small interfering RNA (siRNA-mediated knockdown of IKK1, but not by siRNA-mediated suppression of IKK2. Moreover, IKK1 overexpression augmented 5α-dihydrotestosterone-induced nuclear AR translocation, whereas nuclear AR was reduced by IKK1 knockdown or BMS345541. However, because IKK1 also enhances the activity of a chronically nuclear AR mutant, modulation of the subcellular distribution seems not to be the only mechanism by which IKK1 enhances AR activity. Finally, reduced in vivo AR phosphorylation after BMS345541 treatment and in vitro AR phosphorylation by IKK1 or IKK2 imply that AR constitutes a novel IKK target. Taken together, our data identify IKK1 as a potentially target structure for future therapeutic intervention in PCa.

  6. Androgen receptor CAG polymorphism and sporadic and early-onset prostate cancer among Mexican men.

    Science.gov (United States)

    Gómez, Rocío; Torres-Sánchez, Luisa; Camacho-Mejorado, Rafael; Burguete-García, Ana I; Vázquez-Salas, Ruth Argelia; Martínez-Nava, Gabriela A; Santana, Carla; Noris, Gino

    2016-09-01

    A short CAG repeat length in the gene encoding for the androgen receptor (AR) has been associated with prostate cancer (PC) risk and aggressiveness. In Latino men, information on this association is scarce. Hence, the aim of this study was to evaluate this association in Mexican males. Using fragment analysis by capillary electrophoresis, we determined the number of CAG repeats-(CAG)n-in AR gene from 158 incident PC cases and 326 age-matched healthy controls (±5 years), residing in Mexico City, Mexico. According to Gleason scale and age at diagnosis, cases were classified as high (⩾7) and low grade (<7), as well as early onset (<60 years) or late onset PC (⩾60 years). At diagnosis, 78% of cases were classified as high-grade and 26.6% as early onset. Men with sporadic (no family history of PC) and early-onset PC presented shorter CAG repeat length than controls (18.6±2.2 vs 19.5±2.5; P=0.02). Lower number of CAG repeats (CAG)⩽19 were associated with a greater risk for early-onset PC (odds ratio: 2.31; 95% confidence interval: 1.14-4.69). CAG repeat length could increase the risk for sporadic and early-onset PC. The best cutoff point for identifying at-risk subjects was (CAG)19. However, further studies are necessary to replicate our findings in subjects with a family history of PC and also to evaluate the association between CAG repeats length and disease progression.

  7. Effect of Intermittent Androgen Blockade on the Quality of Life of Patients with Advanced Prostate Carcinoma

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    OBJECTIVE To investigate the effect of intermittent androgen blockade (IAB) on the quality of life (QOL) of patients with advanced prostatic carcinoma (APC).METHODS Investigations on the QOL of 51 APC patients receiving IAB treatment, totaling 3 times, i.e. 6 months before and after, and 12 months after treatment, were perform using the EORTC QLQ-C30 measuring scale and QLQ-PR25 scale.RESULTS Although IAB became an economic burden for the families, it was lessened during the intermission (P<0.05). The overall health status significantly improved 6 months after IAB treatment (P<0.01), especially during the intermission (P<0.05), with a total or local easement of pain (P<0.01) and an improvement of urinary function (P<0.01). Although there was impairment,to various degrees, in many functions of the patients on the 6th month of treatment, such as the physical function (P<0.05), role function (P<0.05), the emotional (P<0.01) and the social functions (P<0.01), with an enhancement of fatigue (P<0.01), these functions gradually recovered by the 12th month as the intermission started. Treatment-related symptoms such as flushing and mammary swelling significantly emerged on the 6th treatment month (P<0.01), and lessened on the 12th (P<0.01). During the treatment period,therewas an notable drop in sexual interest (P<0.01), with a deprivation of sex life, but revived to various degrees during the intermission (P<0.01).CONCLUSION Although IAB treatment of APC patients did impair the physiologic and psychologic status of patients to varying degrees, these were improved and restored during the intermission.

  8. PLCε knockdown inhibits prostate cancer cell proliferation via suppression of Notch signalling and nuclear translocation of the androgen receptor.

    Science.gov (United States)

    Wang, Yin; Wu, Xiaohou; Ou, Liping; Yang, Xue; Wang, Xiaorong; Tang, Min; Chen, E; Luo, Chunli

    2015-06-28

    Phospholipase Cε (PLCε), a key regulator of diverse cellular functions, has been implicated in various malignancies. Indeed, PLCε functions include cell proliferation, apoptosis and malignant transformation. Here, we show that PLCε expression is elevated in prostate cancer (PCa) tissues compared to benign prostate tissues. Furthermore, PLCε depletion using an adenovirally delivered shRNA significantly decreased cell growth and colony formation, arresting the PC3 and LNCaP cell lines in the S phase of the cell cycle. We also observed that PLCε was significantly correlated with Notch1 and androgen receptor (AR). Additionally, we demonstrate that the activation of both the Notch and AR signalling pathways is involved in PLCε-mediated oncogenic effects in PCa. Our findings suggest that PLCε is a putative oncogene and prognostic marker, potentially representing a novel therapeutic target for PCa.

  9. Causes of Mortality After Dose-Escalated Radiation Therapy and Androgen Deprivation for High-Risk Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tendulkar, Rahul D., E-mail: tendulr@ccf.org [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Hunter, Grant K. [Department of Radiation Oncology, Intermountain Healthcare, Salt Lake City, Utah (United States); Reddy, Chandana A.; Stephans, Kevin L.; Ciezki, Jay P.; Abdel-Wahab, May [Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio (United States); Stephenson, Andrew J.; Klein, Eric A. [Department of Urology, Glickman Urological Institute, Cleveland Clinic, Cleveland, Ohio (United States); Mahadevan, Arul [Seacoast Cancer Center New Hampshire, Dover, New Hampshire (United States); Kupelian, Patrick A. [Department of Radiation Oncology, University of California Los Angeles Health System, Los Angeles, California (United States)

    2013-09-01

    Purpose: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. Methods and Materials: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. Results: The median radiation dose was 78 Gy, median duration of AD was 6 months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Conclusions: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not.

  10. Dihydrotestosterone Administration Does Not Increase Intraprostatic Androgen Concentrations or Alter Prostate Androgen Action in Healthy Men: A Randomized-Controlled Trial

    OpenAIRE

    Page, Stephanie T; Lin, Daniel W.; Mostaghel, Elahe A.; Marck, Brett T.; Wright, Jonathan L; Wu, Jennifer; Amory, John K.; Peter S Nelson; Matsumoto, Alvin M.

    2010-01-01

    Exogenous dihydrotestosterone (DHT), which substantially raises serum DHT and lowers serum T, does not significantly alter intraprostatic androgen levels or androgen-responsive gene expression in healthy men.

  11. Contribution of allelic variability in prostate specific antigen (PSA & androgen receptor (AR genes to serum PSA levels in men with prostate cancer

    Directory of Open Access Journals (Sweden)

    Sushant V Chavan

    2014-01-01

    Full Text Available Background & objectives: Wide variability in serum prostate specific antigen (PSA levels exists in malignant conditions of the prostate. PSA is expressed in normal range in 20 to 25 per cent of prostate cancer cases even in presence of high grade Gleason score. This study was aimed to assess the influence of genetic variants exhibited by PSA and androgen receptor (AR genes towards the variable expression of PSA in prostate cancer. Methods: Pre-treatment serum PSA levels from 101 prostate cancer cases were retrieved from medical record. PSA genotype analysis in promoter region and AR gene microsatellite Cytosine/Adenine/Guanine (CAG repeat analysis in exon 1 region was performed using DNA sequencing and fragment analysis techniques. Results: A total of seven single nucleotide polymorphisms (SNPs in the PSA promoter region were noted. Only two SNPs viz., 158G/A (P<0.001 in the proximal promoter region and -3845G/A (P<0.001 in enhancer region showed significant association with serum PSA levels. The carriers of homozygous GG genotype (P<0.001 at both of these polymorphic sites showed higher expression of PSA whereas homozygous AA genotype (P<0.001 carriers demonstrated lower PSA levels. The combination effect of PSA genotypes along with stratified AR CAG repeats lengths (long, intermediate and short was also studied. The homozygous GG genotype along with AR long CAG repeats and homozygous AA genotype along with AR short CAG repeats at position -3845 and -158 showed strong interaction and thus influenced serum PSA levels. Interpretation & conclusions: The genetic variants exhibited by PSA gene at positions -3845G/A and -158G/A may be accountable towards wide variability of serum PSA levels in prostate cancer. Also the preferential binding of G and A alleles at these polymorphic sites along with AR long and short CAG repeats may contribute towards PSA expression.

  12. The ETS domain transcription factor ELK1 directs a critical component of growth signaling by the androgen receptor in prostate cancer cells.

    Science.gov (United States)

    Patki, Mugdha; Chari, Venkatesh; Sivakumaran, Suneethi; Gonit, Mesfin; Trumbly, Robert; Ratnam, Manohar

    2013-04-19

    The androgen receptor (AR) is essential for diverse aspects of prostate development and function. Molecular mechanisms by which prostate cancer (PC) cells redirect AR signaling to genes that primarily support growth are unclear. A systematic search for critical AR-tethering proteins led to ELK1, an ETS transcription factor of the ternary complex factor subfamily. Although genetically redundant, ELK1 was obligatory for AR-dependent growth and clonogenic survival in both hormone-dependent PC and castration-recurrent PC cells but not for AR-negative cell growth. AR required ELK1 to up-regulate a major subset of its target genes that was strongly and primarily enriched for cell growth functions. AR functioned as a coactivator of ELK1 by association through its A/B domain, bypassing the classical mechanism of ELK1 activation by phosphorylation and without inducing ternary complex target genes. The ELK1-AR synergy per se was ligand-independent, although it required ligand for nuclear localization of AR as targeting the AR A/B domain to the nucleus recapitulated the action of hormone; accordingly, Casodex was a poor antagonist of the synergy. ELK3, the closest substitute for ELK1 in structure/function and genome recognition, did not interact with AR. ELK1 thus directs selective and sustained gene induction that is a substantial and critical component of growth signaling by AR in PC cells. The ELK1-AR interaction offers a functionally tumor-selective drug target. PMID:23426362

  13. Changes of prostate gland volume with and without androgen deprivation after intensity modulated radiotherapy - A follow-up study

    International Nuclear Information System (INIS)

    Background and purpose: The shrinking effect of androgen deprivation therapy (ADT) on prostate volume is a known finding, but data on volume changes during radiotherapy are inconsistent. We examined patients with and without ADT undergoing intensity modulated radiotherapy (IMRT) and performed follow-up examinations to study volume changes before and after radiotherapy. Methods and materials: Prostate volumes between planning magnetic resonance imaging (MRI) and last available follow-up MRI were retrospectively determined in 39 patients. Median time interval between first and last MRI was 233 days (range 126-813). Two observers performed volume measurements in consensus and were blind to the timing of MRI. Volume changes over MRI were determined using the ellipsoid formula. Data of patients with and without ADT were compared by a linear mixed model. Results: Of 39 patients, 22 had ADT with a median duration of 5 months (range 1-24). ADT patients showed lower prostate volume throughout the study period (-28% to 38%). Although individual shrinking effect was highly variable, patients treated with IMRT but without ADT showed a significantly larger volume reduction (26.1%) than patients with ADT (12.9%, p < 0.05). Conclusions: Patients undergoing IMRT show definite prostate shrinkage. The rate is slowed down after 6 months in both groups, whereas the volume reduction is significantly larger in patients without ADT. Nevertheless there is no adding effect of ADT + IMRT vs. IMRT alone

  14. Constitutively-active androgen receptor variants function independently of the HSP90 chaperone but do not confer resistance to HSP90 inhibitors.

    Science.gov (United States)

    Gillis, Joanna L; Selth, Luke A; Centenera, Margaret M; Townley, Scott L; Sun, Shihua; Plymate, Stephen R; Tilley, Wayne D; Butler, Lisa M

    2013-05-01

    The development of lethal, castration resistant prostate cancer is associated with adaptive changes to the androgen receptor (AR), including the emergence of mutant receptors and truncated, constitutively active AR variants. AR relies on the molecular chaperone HSP90 for its function in both normal and malignant prostate cells, but the requirement for HSP90 in environments with aberrant AR expression is largely unknown. Here, we investigated the efficacy of three HSP90 inhibitors, 17-AAG, HSP990 and AUY922, against clinically-relevant AR missense mutants and truncated variants. HSP90 inhibition effectively suppressed the signaling of wild-type AR and all AR missense mutants tested. By contrast, two truncated AR variants, AR-V7 and ARv567es, exhibited marked resistance to HSP90 inhibitors. Supporting this observation, nuclear localization of the truncated AR variants was not affected by HSP90 inhibition and AR variant:HSP90 complexes could not be detected in prostate cancer cells. Interestingly, HSP90 inhibition resulted in accumulation of AR-V7 and ARv567es in both cell lines and human tumor explants. Despite the apparent independence of AR variants from HSP90 and their treatment-associated induction, the growth of cell lines with endogenous or enforced expression of AR-V7 or ARv567es remained highly sensitive to AUY922. This study demonstrates that functional AR variant signaling does not confer resistance to HSP90 inhibition, yields insight into the interaction between AR and HSP90 and provides further impetus for the clinical application of HSP90 inhibitors in advanced prostate cancer.

  15. Adverse effects of androgen deprivation therapy in men with prostate cancer: a focus on metabolic and cardiovascular complications

    Institute of Scientific and Technical Information of China (English)

    Lauren Collins; Shehzad Basaria

    2012-01-01

    Prostate cancer (PCa) is the most common malignancy in men.Prostate being an androgen responsive tissue,androgen deprivation therapy (ADT) is used in the management of locally advanced (improves survival) and metastatic (improves pain and quality of life) PCa.Over the past two decades,the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences,though without any evidence of survival advantage.Hypogonadism resulting from ADT is associated with decreased muscle mass and strength,increased fat mass,sexual dysfunction,vasomotor symptoms,decreased quality of life,anemia and bone loss.Insulin resistance,diabetes and cardiovascular disease have recently been added to the list of these complications.As the majority of men with PCa die of conditions other than their primary malignancy,recognition and management of these adverse effects is paramount.Here we review data evaluating metabolic and cardiovascular complications of ADT.

  16. Evaluation of RU58841 as an anti-androgen in prostate PC3 cells and a topical anti-alopecia agent in the bald scalp of stumptailed macaques.

    Science.gov (United States)

    Pan, H J; Wilding, G; Uno, H; Inui, S; Goldsmith, L; Messing, E; Chang, C

    1998-08-01

    The effect of androgen receptor transcriptional activation by RU58841, a nonsteroidal anti-androgen, was studied in the human prostate cancer PC3 cell line by cotransfection with wild-type androgen receptor (wt AR) and an androgen-responsive reporter (MMTV-ARE-CAT) construct. Anti-and rogens, hydroxyflutamide, and Casodex, and the antiestrogen, genistein, were studied in parallel for comparison with RU58841. The wt AR was activated only by the androgen dihydrotestosterone (DHT). Neither the anti-androgens nor antiestrogen can enhance AR transcriptional activity at 10(-11)-10(-7)M in PC3 cells. Hydroxyflutamide, RU58841, and Casodex, but not genistein, displayed competitively suppressive effects on DHT activation of wt AR. The potency of RU58841 was comparable to that of hydroxyflutamide. From this result, topical application of RU58841, which is considered to be a potential therapy for skin diseases, may induce systemic side effects. However, RU58841, on topical application, revealed a potent increase in density, thickening, and length of hair in the macaque model of androgenetic alopecia, whereas no systemic effects were detected. Together our results suggest that RU58841 may have potent antagonism to the wt AR and could be considered as a topically applied active anti-androgen for the treatment of androgen-dependent skin disorders, such as acne, androgenetic alopecia, and hirsutism.

  17. Supra-Additive apoptotic response in predominantly quiescent prostate tumors when treated with androgen ablation and radiotherapy

    International Nuclear Information System (INIS)

    Purpose: Several studies have documented that patients with high risk prostate cancer benefit from androgen ablation (AA) in conjunction with radiotherapy, as compared to those treated with androgen ablation or radiotherapy alone. The hypothesis is that a supra-additive effect is manifested when the treatments are given concomitantly as opposed to sequentially. However, the supra-additivity of this approach is difficult to prove in clinical trials due to tumor heterogeneity and because it takes over 6 years to obtain meaningful data on survival differences. Moreover, under certain conditions androgen ablation might induce quiescence (a more radioresistant state), resulting in a sub-additive interaction. For these reasons, we investigated the effects of androgen ablation and radiation using the androgen sensitive R3327-G Dunning rat prostate model. Materials and Methods: The R3327-G tumor line was used in the 23rd-24th in vivo transplant generations. The tumors were grown in the flanks of 250-300g male Copenhagen rats and were used when they reached approximately 1 cc. The growth fraction was determined by continuously labelling the tumors in vivo with chlorodeoxyuridine (CldUrd) via Alzet minipumps implanted in the opposite flank and measuring the incorporated CldUrd and DNA by flow cytometry. Pulse labelling with iododeoxyuridine (IdUrd) to determine the cell kinetic parameters of labelling index (LI), length of S-phase (Ts), and potential doubling time (Tpot) was accomplished by intraperitoneal injection; these parameters were also calculated from flow cytometric data. Apoptotic index was quantified using an immunohistochemical deoxynucleotidyl transferase (TUNEL) assay on formalin-fixed paraffin-embedded tissue; 2000 cells (20 or more high powered fields) were counted per tumor. Results: Tumor volume measurements revealed that the doubling time (Td) increased from an average of 10 d in intact rats to 37 d in castrates. The pulse labelling of tumors with IdUrd at

  18. Mature Results of the Ottawa Phase II Study of Intermittent Androgen-Suppression Therapy in Prostate Cancer: Clinical Predictors of Outcome

    International Nuclear Information System (INIS)

    Purpose: To present the mature experience of a phase II trial of intermittent androgen suppression (IAS). Methods and Materials: Intermittent androgen-suppression therapy was initiated in prostate-cancer patients to delay hormone resistance and minimize potential side effects of androgen-deprivation therapy (ADT). Patients received cyclical periods of ADT and observation (off-treatment interval [OTI]). Androgen-deprivation therapy was reinitiated when the level of prostate-specific antigen (PSA) rose above 10 ng/ml, or for disease progression. Associations between clinical factors and eligibility for OTI were measured. Kaplan-Meier and Cox regression analyses were used to determine factors predicting the duration of OTIs. Results: Ninety-five patients completed 187 cycles of treatment. The median duration of OTIs was 8.5 months. Patients with higher PSA and metastatic disease were less likely to be eligible for the first OTI (p < 0.01). In multivariate analysis, patients with higher PSA and local relapse had significantly longer OTIs (p < 0.01) compared with metastatic patients. The median time to withdrawal from the study was 37 months. Conclusions: Intermittent androgen suppression appears to be a favorable treatment option for patients with biochemically (according to level of PSA) or locally recurrent prostate cancer with favorable long-term survival, a high probability of eligibility for OTIs, and durable OTIs

  19. Androgen receptor splice variant 7 (AR-V7) and drug efficacy in castration-resistant prostate cancer: Biomarker for treatment selection exclusion or inclusion?

    Science.gov (United States)

    Leibrand, Crystal R; Price, Douglas K; Figg, William D

    2016-05-01

    Currently there are no molecular biomarkers used to help guide treatment selection for those patients with castration-resistant prostate cancer. A recent study published in JAMA Oncology (Antonarakis et al.) presents evidence supporting the potential use of androgen receptor splice variant 7 as a biomarker for optimal treatment selection in this population.

  20. Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Hu; Zhu, Chen; Qin, Chao [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Tao, Tao [Department of Neurosurgery, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Li, Jie; Cheng, Gong; Li, Pu; Cao, Qiang; Meng, Xiaoxin; Ju, Xiaobing; Shao, Pengfei; Hua, Lixin [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Gu, Min, E-mail: medzhao1980@163.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China); Yin, Changjun, E-mail: drcjyin@gmail.com [State Key Laboratory of Reproductive Medicine, Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing (China)

    2013-03-08

    Highlights: ► Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells. ► Fenofibrate reduces the expressions of androgen receptor in LNCaP cells. ► Fenofibrate induces oxidative stress in the prostate cancer cell line LNCaP. -- Abstract: Fenofibrate, a peroxisome proliferator-androgen receptor-alpha agonist, is widely used in treating different forms of hyperlipidemia and hypercholesterolemia. Recent reports have indicated that fenofibrate exerts anti-proliferative and pro-apoptotic properties. This study aims to investigate the effects of fenofibrate on the prostate cancer (PCa) cell line LNCaP. The effects of fenofibrate on LNCaP cells were evaluated by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, Western blot analysis, and dual-luciferase reporter assay. Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells, reduces the expressions of androgen receptor (AR) and AR target genes (prostate-specific antigen and TMPRSS2), and inhibits Akt phosphorylation. Fenofibrate can induce the accumulation of intracellular reactive oxygen species and malondialdehyde, and decrease the activities of total anti-oxidant and superoxide dismutase in LNCaP cells. Fenofibrate exerts an anti-proliferative property by inhibiting the expression of AR and induces apoptosis by causing oxidative stress. Therefore, our data suggest fenofibrate may have beneficial effects in fenofibrate users by preventing prostate cancer growth through inhibition of androgen activation and expression.

  1. Androgen deprivation therapy for volume reduction, lower urinary tract symptom relief and quality of life improvement in patients with prostate cancer

    DEFF Research Database (Denmark)

    Axcrona, Karol; Aaltomaa, Sirpa; da Silva, Carlos Martins;

    2012-01-01

    Study Type--Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Androgen deprivation therapy (ADT) is commonly used as a primary treatment for patients with prostate cancer (PCa) who are not eligible for radical treatment options. ADT is also used in pati...

  2. Fenofibrate down-regulates the expressions of androgen receptor (AR) and AR target genes and induces oxidative stress in the prostate cancer cell line LNCaP

    International Nuclear Information System (INIS)

    Highlights: ► Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells. ► Fenofibrate reduces the expressions of androgen receptor in LNCaP cells. ► Fenofibrate induces oxidative stress in the prostate cancer cell line LNCaP. -- Abstract: Fenofibrate, a peroxisome proliferator-androgen receptor-alpha agonist, is widely used in treating different forms of hyperlipidemia and hypercholesterolemia. Recent reports have indicated that fenofibrate exerts anti-proliferative and pro-apoptotic properties. This study aims to investigate the effects of fenofibrate on the prostate cancer (PCa) cell line LNCaP. The effects of fenofibrate on LNCaP cells were evaluated by flow cytometry, reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, Western blot analysis, and dual-luciferase reporter assay. Fenofibrate induces cell cycle arrest in G1 phase and apoptosis in LNCaP cells, reduces the expressions of androgen receptor (AR) and AR target genes (prostate-specific antigen and TMPRSS2), and inhibits Akt phosphorylation. Fenofibrate can induce the accumulation of intracellular reactive oxygen species and malondialdehyde, and decrease the activities of total anti-oxidant and superoxide dismutase in LNCaP cells. Fenofibrate exerts an anti-proliferative property by inhibiting the expression of AR and induces apoptosis by causing oxidative stress. Therefore, our data suggest fenofibrate may have beneficial effects in fenofibrate users by preventing prostate cancer growth through inhibition of androgen activation and expression

  3. Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency

    Directory of Open Access Journals (Sweden)

    Yeh Cheng-Yu

    2009-12-01

    Full Text Available Abstract Background Prostate cancer is a world wide leading cancer and it is characterized by its aggressive metastasis. According to the clinical heterogeneity, prostate cancer displays different stages and grades related to the aggressive metastasis disease. Although numerous studies used microarray analysis and traditional clustering method to identify the individual genes during the disease processes, the important gene regulations remain unclear. We present a computational method for inferring genetic regulatory networks from micorarray data automatically with transcription factor analysis and conditional independence testing to explore the potential significant gene regulatory networks that are correlated with cancer, tumor grade and stage in the prostate cancer. Results To deal with missing values in microarray data, we used a K-nearest-neighbors (KNN algorithm to determine the precise expression values. We applied web services technology to wrap the bioinformatics toolkits and databases to automatically extract the promoter regions of DNA sequences and predicted the transcription factors that regulate the gene expressions. We adopt the microarray datasets consists of 62 primary tumors, 41 normal prostate tissues from Stanford Microarray Database (SMD as a target dataset to evaluate our method. The predicted results showed that the possible biomarker genes related to cancer and denoted the androgen functions and processes may be in the development of the prostate cancer and promote the cell death in cell cycle. Our predicted results showed that sub-networks of genes SREBF1, STAT6 and PBX1 are strongly related to a high extent while ETS transcription factors ELK1, JUN and EGR2 are related to a low extent. Gene SLC22A3 may explain clinically the differentiation associated with the high grade cancer compared with low grade cancer. Enhancer of Zeste Homolg 2 (EZH2 regulated by RUNX1 and STAT3 is correlated to the pathological stage

  4. [11C]choline uptake with PET/CT for the initial diagnosis of prostate cancer: relation to PSA levels, tumour stage and anti-androgenic therapy

    International Nuclear Information System (INIS)

    The accuracy of positron emission tomography (PET)/CT with [11C]choline for the detection of prostate cancer is not well established. We assessed the dependence of [11C]choline maximum standardized uptake values (SUVmax) in the prostate gland on cell malignancy, prostate-specific antigen (PSA) levels, Gleason score, tumour stage and anti-androgenic hormonal therapy. In this prospective study, PET/CT with [11C]choline was performed in 19 prostate cancer patients who subsequently underwent prostatectomy with histologic sextant analysis (group A) and in six prostate cancer patients before and after anti-androgenic hormonal therapy (bicalutamide 150 mg/day; median treatment of 4 months; group B). In group A, based on a sextant analysis with a [11C]choline SUVmax cutoff of 2.5 (as derived from a receiver-operating characteristic analysis), PET/CT showed sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 72, 43, 64, 51 and 60%, respectively. In the patient-by-patient analysis, no significant correlation was detected between SUVmax and PSA levels, Gleason score or pathological stage. On the contrary, a significant (P max and anti-androgenic therapy both in univariate (r 2 = 0.24) and multivariate (r 2 = 0.48) analyses. Prostate [11C]choline uptake after bicalutamide therapy significantly (P 11C]choline is not suitable for the initial diagnosis and local staging of prostate cancer. PET/CT with [11C]choline could be used to monitor the response to anti-androgenic therapy. (orig.)

  5. [Fluorine-18 labeled androgens and progestins; imaging agents for tumors of prostate and breast]: Technical progress report, February 1, 1987-January 31, 1988

    International Nuclear Information System (INIS)

    This project develops fluorine-18 labeled steroids that possess high binding affinity and selectivity for androgen and progesterone receptors and can be used as positron-emission tomographic imaging agents for prostate tumors and breast tumors, respectively. These novel diagnostic agents may enable an accurate estimation of tumor dissemination, such as metastasis of prostate cancer and lymph node involvement of breast cancer, and an in vivo determination of the endocrine responsiveness of these tumors. They will provide essential information for the selection of alternative therapies thereby improving the management of prostate and breast cancer patients. 14 refs., 1 tab

  6. Disruption of androgen and estrogen receptor activity in prostate cancer by a novel dietary diterpene carnosol: implications for chemoprevention

    Science.gov (United States)

    Johnson, Jeremy J.; Syed, Deeba N.; Suh, Yewseok; Heren, Chenelle R.; Saleem, Mohammad; Siddiqui, Imtiaz A.; Mukhtar, Hasan

    2010-01-01

    Emerging data is suggesting that estrogens, in addition to androgens, may also be contributing to the development of prostate cancer (PCa). In view of this notion agents that target estrogens, in addition to androgens, may be a novel approach for PCa chemoprevention and treatment. Thus, the identification and development of non-toxic dietary agents capable of disrupting androgen receptor (AR) in addition to estrogen receptor (ER) could be extremely useful in the management of PCa. Through molecular modeling we found carnosol, a dietary diterpene fits within the ligand binding domain of both AR and ER-α. Using a TR-FRET assay we found that carnosol interacts with both AR and ER-α and additional experiments confirmed that it functions as a receptor antagonist with no agonist effects. LNCaP, 22Rv1, and MCF7 cells treated with carnosol (20–40 µM) showed decreased protein expression of AR and ER-α. Oral administration of carnosol at 30 mg/kg five days weekly for 28 days to 22Rv1 PCa xenografted mice suppressed tumor growth by 36% (p = 0.028) and was associated with a decrease in serum PSA by 26% (p=0.0042). These properties make carnosol unique to any known anti-androgen or anti-estrogen investigated so far for the simultaneous disruption of AR and ER-α. We suggest that carnosol may be developed or chemically modified through more rigorous structure activity relationship studies for a new class of investigational agents - a dual AR/ER modulator. PMID:20736335

  7. AB125. Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality

    Science.gov (United States)

    Niu, Yuanjie; Zhu, Shimiao

    2015-01-01

    Background There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM). Methods and findings We performed a meta-analysis from population-based observational studies comparing ADT vs control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. 6 studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR =1.10, 95% CIs: 1.00-1.21; P=0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR =1.19, 95% CIs: 1.04-1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR =1.46, 95% CIs: 1.03-2.08; P=0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled result suggested that ADT was associated with CVM (HR =1.17, 95% CIs: 1.04-1.32; P=0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g., prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR =1.19, 95% CIs: 1.08-1.30; P<0.001) and CVM (HR =1.30, 95% CIs: 1.13-1.50; P<0.001) were found in men treated with ADT monotherapy. Conclusions ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.

  8. AB187. Androgen deprivation therapy for prostate cancer is associated with cardiovascular morbidity and mortality

    Science.gov (United States)

    Niu, Yuanjie; Zhu, Shimiao

    2016-01-01

    Objectives There is no consensus regarding whether androgen deprivation therapy (ADT) is associated with cardiovascular disease (CVD) and cardiovascular mortality (CVM). The objective of this study was to determine the role of ADT for prostate cancer (PCa) in development of cardiovascular events (CVD and CVM). Methods We performed a meta-analysis from population-based observational studies comparing ADT vs. control aimed at treating PCa in patients with PCa, reporting either CVD or CVM as outcome. Publications were searched using Medline, Embase, Cochrane Library Central Register of observational studies database up to May 31th 2014, and supplementary searches in publications from potentially relevant journals. Six studies were identified with a total of 129,802 ADT users and 165,605 controls investigating the relationship between ADT and CVD. Result The incidence of CVD was 10% higher in ADT groups, although no significant association was observed (HR =1.10, 95% CIs, 1.00–1.21; P=0.06). For different types of ADT, CVD was related with gonadotropin-releasing hormone (GnRH) (HR =1.19, 95% CIs, 1.04–1.36; P<0.001) and GnRH plus oral antiandrogen (AA) (HR =1.46, 95% CIs, 1.03–2.08; P=0.04), but not with AA alone or orchiectomy. For CVM, 119,625 ADT users and 150,974 controls from 6 eligible studies were included, pooled result suggested that ADT was associated with CVM (HR=1.17, 95% CIs, 1.04–1.32; P=0.01). Significantly increased CVM was also detected in GnRH and GnRH plus AA groups. When patients received other treatments (e.g., prostatectomy and radiotherapy) were ruled out of consideration, more increased CVD (HR =1.19, 95% CIs, 1.08–1.30; P<0.001) and CVM (HR =1.30, 95% CIs, 1.13–1.50; P<0.001) were found in men treated with ADT monotherapy. Conclusions ADT is associated with both CVD and CVM. Particularly, GnRH alone and GnRH plus AA can significantly increase the incidence of cardiovascular events in patients with PCa.

  9. Usefulness of J-CAPRA score for high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy

    International Nuclear Information System (INIS)

    A novel risk assessment method, Japan Cancer of the Prostate Risk Assessment, has been developed based on database of patients receiving primary androgen deprivation therapy. To investigate the usefulness of Japan Cancer of the Prostate Risk Assessment for non-metastatic, high-risk prostate cancer patients treated with carbon ion radio-therapy plus androgen deprivation therapy. Patients with non-metastatic, high-risk prostate cancer (T3, initial prostate specific antigen level ≥20 ng/ml, and/or Gleason score ≥8) were included. The patients were treated with carbon ion radiotherapy (the total dose from 57.6 Gy (relative biological effectiveness)/16 fractions to 66.0 Gy (relative biological effectiveness)/20 fractions), and neoadjuvant as well as adjuvant androgen deprivation therapy for at least 24 months. Four hundred and twenty-six patients were included with the median follow-up of 68.1 months. Of 426, 210 (49.3%), 270 (63.4%) and 251 (58.9%) had Gleason 8-10, prostate specific antigen ≥20 ng/ml and T3, respectively. The 10-year progression-free and cause-specific survival rates in Japan Cancer of the Prostate Risk Assessment 1-2 group (76.5 and 98.9%) were significantly better than those in Japan Cancer of the Prostate Risk Assessment 3-6 group (52.6 and 93.1%), (P < 0.001 and P=0.044, respectively). The median progression-free survivals in the Japan Cancer of the Prostate Risk Assessment 1-2 and 3-6 groups were 158.9 months and 125.9 months (95% confidence interval: 108.6-143.2 months), respectively. For non-metastatic, high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy, Japan Cancer of the Prostate Risk Assessment score was useful for predicting the progression-free and cause-specific survivals. (author)

  10. The Prevalence of Cardiac Risk Factors in Men with Localized Prostate Cancer Undergoing Androgen Deprivation Therapy in British Columbia, Canada

    Directory of Open Access Journals (Sweden)

    Margot K. Davis

    2015-01-01

    Full Text Available Background. While androgen deprivation therapy (ADT reduces the risk of prostate cancer-specific mortality in high-risk localized prostate cancer, it adversely affects cardiovascular (CV risk factor profiles in treated men. Methods. We retrospectively reviewed the charts of 100 consecutive men with intermediate- or high-risk localized prostate cancer referred to the British Columbia Cancer Agency for ADT. Data on CV risk factors and disease were collected and Framingham risk scores were calculated. Results. The median age of the study cohort was 73 years. Established cardiovascular disease was present in 25% of patients. Among patients without established CV disease, calculated Framingham risk was high in 65%, intermediate in 33%, and low in 1%. Baseline hypertension was present in 58% of patients, dyslipidemia in 51%, and diabetes or impaired glucose tolerance in 24%. Hypertension was more prevalent in the study cohort than in an age- and sex-matched population sample (OR 1.74, P=0.006; diabetes had a similar prevalence (OR 0.93, P=0.8. Conclusions. Patients receiving ADT have a high prevalence of cardiovascular disease and risk factors and are more likely to be hypertensive than population controls. Low rates of CV risk screening suggest opportunities for improved primary and secondary prevention of CV disease in this population.

  11. Predictors of Fracture Risk and Bone Mineral Density in Men with Prostate Cancer on Androgen Deprivation Therapy

    Directory of Open Access Journals (Sweden)

    Katherine Neubecker

    2011-01-01

    Full Text Available Decrease of bone mineral density (BMD and fracture risk is increased in men with prostate cancer receiving androgen deprivation therapy (ADT. We looked at possible predictors of decreased BMD and increased fracture risk in men with prostate cancer; most of whom were on ADT. In a retrospective study, we analyzed serum, BMD, and clinical risk factors used in the Fracture Risk Assessment (FRAX tool and others in 78 men with prostate cancer with reported height loss. The subjects were divided in two groups: 22 men with and 56 without vertebral fractures. 17 of the 22 men with vertebral fractures on spine X-rays did not know they had a vertebral fracture. Of those 17 men, 9 had not previously qualified for treatment based on preradiograph FRAX score calculated with BMD, and 6 based on FRAX calculated without BMD. Performing spine films increased the predictive ability of FRAX for vertebral fracture. Vertebral fracture was better predicted by FRAX for other osteoporotic fractures than FRAX for hip fractures. The inclusion of BMD in FRAX calculations did not affect the predictive ability of FRAX. The PSA level showed a positive correlation with lumbar spine BMD and accounted for about 9% of spine BMD.

  12. Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7) Detection from Prostate Cancer Patient Blood Biopsies

    Science.gov (United States)

    Ma, Yafeng; Luk, Alison; Young, Francis P.; Lynch, David; Chua, Wei; Balakrishnar, Bavanthi; de Souza, Paul; Becker, Therese M.

    2016-01-01

    Androgen receptor splice variant V7 (AR-V7) was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs): We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR) to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa) patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs) or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies. PMID:27527157

  13. Droplet Digital PCR Based Androgen Receptor Variant 7 (AR-V7 Detection from Prostate Cancer Patient Blood Biopsies

    Directory of Open Access Journals (Sweden)

    Yafeng Ma

    2016-08-01

    Full Text Available Androgen receptor splice variant V7 (AR-V7 was recently identified as a valuable predictive biomarker in metastatic castrate-resistant prostate cancer. Here, we report a new, sensitive and accurate screen for AR-V7 mRNA expression directly from circulating tumor cells (CTCs: We combined EpCAM-based immunomagnetic CTC isolation using the IsoFlux microfluidic platform with droplet digital polymerase chain reaction (ddPCR to analyze total AR and AR-V7 expression from prostate cancer patients CTCs. We demonstrate that AR-V7 is reliably detectable in enriched CTC samples with as little as five CTCs, even considering tumor heterogeneity, and confirm detection of AR-V7 in CTC samples from advanced prostate cancer (PCa patients with AR-V7 detection limited to castrate resistant disease status in our sample set. Sensitive molecular analyses of circulating tumor cells (CTCs or circulating tumor nucleic acids present exciting strategies to detect biomarkers, such as AR-V7 from non-invasive blood samples, so-called blood biopsies.

  14. High CD10 expression in lymph node metastases from surgically treated prostate cancer independently predicts early death.

    Science.gov (United States)

    Fleischmann, Achim; Rocha, Carla; Saxer-Sekulic, Nikolina; Zlobec, Inti; Sauter, Guido; Thalmann, George N

    2011-06-01

    Patients with nodal positive prostate cancers are an important cohort with poorly defined risk factors. CD10 is a cell surface metallopeptidase that has been suggested to play a role in prostate cancer progression. CD10 expression was evaluated in 119 nodal positive prostate cancer patients using tissue microarrays constructed from primary tumors and lymph node metastases. All patients underwent radical prostatectomy and standardized extended lymphadenectomy. They had no neoadjuvant therapy and received deferred androgen deprivation. In the primary tumor, high CD10 expression was significantly associated with earlier death from disease when compared with low CD10 expression (5-year survival 73.7% vs. 91.8%; p = 0.043). In the metastases, a high CD10 expression was significantly associated with larger total size of metastases (median 11.4 vs. 6.5 mm; p = 0.015), earlier death of disease (5-year survival 71.5% vs. 87.3%; p = 0.017), and death of any cause (5-year survival 70.0% vs. 87.2%; p = 0.001) when compared with low CD10 expression. CD10 expression in the metastases added independent prognostic information for overall survival (p = 0.029) after adjustment for Gleason score of the primary tumor, nodal tumor burden, and resection margins. In conclusion, a high CD10 expression in prostate cancer predicts early death. This information is inherent in the primary tumors and in the lymph node metastases and might help to personalize patient management.

  15. A competitive inhibitor that reduces recruitment of androgen receptor to androgen-responsive genes.

    Science.gov (United States)

    Cherian, Milu T; Wilson, Elizabeth M; Shapiro, David J

    2012-07-01

    The androgen receptor (AR) has a critical role in the growth and progression of androgen-dependent and castration-resistant prostate cancers. To identify novel inhibitors of AR transactivation that block growth of prostate cancer cells, a luciferase-based high-throughput screen of ~160,000 small molecules was performed in cells stably expressing AR and a prostate-specific antigen (PSA)-luciferase reporter. CPIC (1-(3-(2-chlorophenoxy) propyl)-1H-indole-3-carbonitrile) was identified as a small molecule that blocks AR transactivation to a greater extent than other steroid receptors. CPIC inhibited AR-mediated proliferation of androgen-sensitive prostate cancer cell lines, with minimal toxicity in AR-negative cell lines. CPIC treatment also reduced the anchorage-independent growth of LAPC-4 prostate cancer cells. CPIC functioned as a pure antagonist by inhibiting the expression of AR-regulated genes in LAPC-4 cells that express wild-type AR and exhibited weak agonist activity in LNCaP cells that express the mutant AR-T877A. CPIC treatment did not reduce AR levels or alter its nuclear localization. We used chromatin immunoprecipitation to identify the site of action of CPIC. CPIC inhibited recruitment of androgen-bound AR to the PSA promoter and enhancer sites to a greater extent than bicalutamide. CPIC is a new therapeutic inhibitor that targets AR-mediated gene activation with potential to arrest the growth of prostate cancer.

  16. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Davis Rodney

    2006-07-01

    Full Text Available Abstract Background Prostate cancer cells communicate reciprocally with the stromal cells surrounding them, inside the prostate, and after metastasis, within the bone. Each tissue secretes factors for interpretation by the other. One stromally-derived factor, Hepatocyte Growth Factor (HGF, was found twenty years ago to regulate invasion and growth of carcinoma cells. Working with the LNCaP prostate cancer progression model, we found that these cells could respond to HGF stimulation, even in the absence of Met, the only known HGF receptor. The new HGF binding partner we find on the cell surface may help to clarify conflicts in the past literature about Met expression and HGF response in cancer cells. Methods We searched for Met or any HGF binding partner on the cells of the PC3 and LNCaP prostate cancer cell models, using HGF immobilized on agarose beads. By using mass spectrometry analyses and sequencing we have identified nucleolin protein as a novel HGF binding partner. Antibodies against nucleolin (or HGF were able to ameliorate the stimulatory effects of HGF on met-negative prostate cancer cells. Western blots, RT-PCR, and immunohistochemistry were used to assess nucleolin levels during prostate cancer progression in both LNCaP and PC3 models. Results We have identified HGF as a major signaling component of prostate stromal-conditioned media (SCM and have implicated the protein nucleolin in HGF signal reception by the LNCaP model prostate cancer cells. Antibodies that silence either HGF (in SCM or nucleolin (on the cell surfaces eliminate the adhesion-stimulatory effects of the SCM. Likewise, addition of purified HGF to control media mimics the action of SCM. C4-2, an LNCaP lineage-derived, androgen-independent human prostate cancer cell line, responds to HGF in a concentration-dependent manner by increasing its adhesion and reducing its migration on laminin substratum. These HGF effects are not due to shifts in the expression levels of

  17. Androgen-induced cell migration: role of androgen receptor/filamin A association.

    Directory of Open Access Journals (Sweden)

    Gabriella Castoria

    Full Text Available BACKGROUND: Androgen receptor (AR controls male morphogenesis, gametogenesis and prostate growth as well as development of prostate cancer. These findings support a role for AR in cell migration and invasiveness. However, the molecular mechanism involved in AR-mediated cell migration still remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: Mouse embryo NIH3T3 fibroblasts and highly metastatic human fibrosarcoma HT1080 cells harbor low levels of transcriptionally incompetent AR. We now report that, through extra nuclear action, AR triggers migration of both cell types upon stimulation with physiological concentrations of the androgen R1881. We analyzed the initial events leading to androgen-induced cell migration and observed that challenging NIH3T3 cells with 10 nM R1881 rapidly induces interaction of AR with filamin A (FlnA at cytoskeleton. AR/FlnA complex recruits integrin beta 1, thus activating its dependent cascade. Silencing of AR, FlnA and integrin beta 1 shows that this ternary complex controls focal adhesion kinase (FAK, paxillin and Rac, thereby driving cell migration. FAK-null fibroblasts migrate poorly and Rac inhibition by EHT impairs motility of androgen-treated NIH3T3 cells. Interestingly, FAK and Rac activation by androgens are independent of each other. Findings in human fibrosarcoma HT1080 cells strengthen the role of Rac in androgen signaling. The Rac inhibitor significantly impairs androgen-induced migration in these cells. A mutant AR, deleted of the sequence interacting with FlnA, fails to mediate FAK activation and paxillin tyrosine phosphorylation in androgen-stimulated cells, further reinforcing the role of AR/FlnA interaction in androgen-mediated motility. CONCLUSIONS/SIGNIFICANCE: The present report, for the first time, indicates that the extra nuclear AR/FlnA/integrin beta 1 complex is the key by which androgen activates signaling leading to cell migration. Assembly of this ternary complex may control organ development

  18. Correction of androgen deficiency in chronic infectious prostatitis as pathogenetic method of overcoming inefficiencies standard antibiotics against the growing antibiotic resistance

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2014-11-01

    Full Text Available The chronic prostatitis occupies the big relative density in structure of an out-patient urological pathology in our country, however, results of its standard pharmacotherapy remain unsatisfactory that is accompanied by high risk clinical recurrence and progressing of anatomic and functional disorders in prostata. Modern methods of diagnostics of the chronic infectious prostatitis, which share in the general structure of inflammatory prostata diseases does not exceed 10 %, are based on the recommended volume of the standard tests directed only on revealing of the infectious agent in a prostatic secret, and do not consider degree of disorders of the prostatic homeostasis which key moment is prostata androgen-dependence. It leads to mainly symptomatic approach in treatment of a chronic infectious prostatitis in the modern urological practice, based exclusively on antibacterial therapy that promotes the further growth of prostate pathogens antibiotics resistance, inefficiencies of unreasonable repeated courses of antibacterial therapy and are supported by a myth about incurability of a chronic prostatitis. At the same time, intraprostatic androgen balance defines all basic functions of gland, and its safety essentially depends on testosterone blood level, therefore endogenic testosterone level it is possible to consider as universal predictor of prostata metabolic homeostasis disorders, leading to decrease in bactericidal function of gland and infections. This author’s concept allows to consider correction of an adverse hormonal and metabolic background on which the clinical picture of a chronic prostatitis (first of all, deficiency of sexual hormones as pathogenetic therapy of all infectious chronic prostatitises against which realisation of effects of antibacterial therapy is essentially facilitated is developed or last is not so necessary, to what own clinical supervision resulted in article testify. Such interdisciplinary approach will lead

  19. Correction of androgen deficiency in chronic infectious prostatitis as pathogenetic method of overcoming inefficiencies standard antibiotics against the growing antibiotic resistance

    Directory of Open Access Journals (Sweden)

    I. A. Tyuzikov

    2013-01-01

    Full Text Available The chronic prostatitis occupies the big relative density in structure of an out-patient urological pathology in our country, however, results of its standard pharmacotherapy remain unsatisfactory that is accompanied by high risk clinical recurrence and progressing of anatomic and functional disorders in prostata. Modern methods of diagnostics of the chronic infectious prostatitis, which share in the general structure of inflammatory prostata diseases does not exceed 10 %, are based on the recommended volume of the standard tests directed only on revealing of the infectious agent in a prostatic secret, and do not consider degree of disorders of the prostatic homeostasis which key moment is prostata androgen-dependence. It leads to mainly symptomatic approach in treatment of a chronic infectious prostatitis in the modern urological practice, based exclusively on antibacterial therapy that promotes the further growth of prostate pathogens antibiotics resistance, inefficiencies of unreasonable repeated courses of antibacterial therapy and are supported by a myth about incurability of a chronic prostatitis. At the same time, intraprostatic androgen balance defines all basic functions of gland, and its safety essentially depends on testosterone blood level, therefore endogenic testosterone level it is possible to consider as universal predictor of prostata metabolic homeostasis disorders, leading to decrease in bactericidal function of gland and infections. This author’s concept allows to consider correction of an adverse hormonal and metabolic background on which the clinical picture of a chronic prostatitis (first of all, deficiency of sexual hormones as pathogenetic therapy of all infectious chronic prostatitises against which realisation of effects of antibacterial therapy is essentially facilitated is developed or last is not so necessary, to what own clinical supervision resulted in article testify. Such interdisciplinary approach will lead

  20. Targeted-cryosurgical ablation of the prostate with androgen deprivation therapy: quality of life in high-risk prostate cancer patients

    Institute of Scientific and Technical Information of China (English)

    Seok-Ho Kang; Jin-Wook Kim; Jae-Hyun Bae; Hong-Seok Park; Du-Geon Moon; Duck-Ki Yoon; Jun Cheon; Je-Jong Kim

    2006-01-01

    Aim: To present preliminary results on health-related quality of life (QoL), prostate-associated symptoms and therapeutic effects of targeted-cryosurgical ablation of the prostate (TCSAP) with androgen deprivation therapy (ADT) in high-risk prostate cancer (PCa) patients. Methods: Thirty-four men with high-risk PCa features underwent TCSAP,and ADT was added to improve the treatment outcomes. High-risk parameters were defined as either prostatespecific antigen (PSA) ≥ 10ng/mL, or Gleason score ≥ 8, or both. The Genito-Urinary Group of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) with prostate-cancer-specific module (QLQ-PR25) was used for evaluating morbidities and PSA levels were recorded every 3 months. PSA failure was defined as the inability to reach a nadir of 0.4 ng/mL or less. Results: Although it was not statistically significant, the global health status scores increased after TCSAP with ADT. The scores for five functional scales also became higher after treatment. The most prominent symptom after treatment was sexual dysfunction, followed by treatment-related and irritative voiding symptoms. Conclusion: TCSAP with ADT appears to be minimally invasive with high QoL except for sexual dysfunction. Long-term follow-up of PSA data and survival is necessary before any conclusions can be made on the efficacy of this promising new therapeutic modality in the treatment of PCa.

  1. Locally advanced prostate cancer: combination of high-dose high-precision radiotherapy and androgen deprivation therapy%Locally advanced prostate cancer:combination of high-dose high-precision radiotherapy and androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    Michel Bolla; René-Olivier Mirimanoff

    2014-01-01

    Locally advanced prostate cancer entails a risk of local,regional and systemic relapse requiring the combination of a Ioco-regional treatment,namely external beam radiotherapy(EBRT) to control the pelvic-confined disease,combined with a systemic therapy,namely androgen-deprivation therapy(ADT),to potentiate irradiation and to destroy the infra-clinical androgen-dependant disease outside the irradiated volume.Many phases Ⅲ randomized trials have paved the way in establishing the indications of this combined approach,which requires a long term ADT(≥2 years) with LHRH agonists.The duration of ADT may be reduced to 6 months should there be a significant comorbidity,a reluctance from the patient or a poor tolerance.A multidisciplinary approach will enable physicians to tailor the treatment strategy and a close cooperation between the specialists and the general practitioners will be set up to prevent as much as possible the side-effects of ADT.

  2. What is appropriate neoadjuvant/adjuvant androgen deprivation for high-risk/locally advanced prostate cancer?

    Institute of Scientific and Technical Information of China (English)

    Mikio Namiki; Hiroyuki Konaka

    2011-01-01

    @@ The majority of low-risk patients with clinically localized prostate cancer have a high likelihood of disease-free survival,regardless of the treatment option chosen.1 In contrast, patients with high-risk prostate cancer with high Gleason score, elevated prostate-specific antigen level and advanced clinical stage have a high probability of treatment failure after initial management by single-treatment modalities, such as radical pro-statectomy (RP), external beam radiation therapy (EBRT) or brachytherapy.2,3 Therefore, it is extremely important to establish the most effective treatment strategy for patients with high-risk prostate cancer.

  3. Differential regulation of glutathione S—transferase Yb1 mRNA levels in rat prostate,liver and brain by androgen

    Institute of Scientific and Technical Information of China (English)

    ZHANGYUAN; CHAWNSHANGCHANG; 等

    1995-01-01

    Northern blot analysis of glutathione S-transferase (GST)Yb1 mRNA in different tissues of male and female rate revealed that its tissue-specific transcription patterns were highly sex hormone related.Although the GST Yb1 mRNA could be detected in most of the tissues examined at various levels,the highest abundance was observed in the ventral prostate,uterus and liver,which were the main the ventral prostate,uterus and liver,which were the main target tissue for androgen,estrogen and glucocorticoid respectively.The effect of androgen on the transcription of GST YB1 was also tissue-specific.Since androgen with drawal by castration caused the up-regulation of GST Yb1 mRNA in the ventral prostate but down-regulation in the liver and no effect in the brain,evalution of this system for studying the regulation mechanisms of gene expression by which androgen exerts its differential effects has been discussed.

  4. Nuclear androgen receptors in human prostatic tissue. Extraction with heparin and estimation of the number of binding sites with different methods

    International Nuclear Information System (INIS)

    A procedure for the estimation of nuclear androgen receptors in benign prostatic hyperplastic tissue is described, which employs extraction of receptors from nuclei with buffers containing heparin. Extraction of a nuclear pellet with a heparin-containing (1 g/l) buffer appeared to have definite advantages over 0.4 mol/l KCl extraction. Heparin appeared to be twice as efficient in extracting androgen receptors. In addition aggregated receptor proteins, formed after storage at -800C, were partly deaggregated by heparin. Specific isolation of the androgen receptor was performed using either agar gel electrophoresis, protamine sulphate precipitation or LH-20 gel filtration. A comparison was made between the amounts of estimated receptors with these different techniques. Protamine sulphate precipitation resulted in the highest estimates of receptor-bound 5α-[3H]dihydrotestosterone (3H-DHT). Treatment of the labelled nuclear extracts with a charcoal suspension prior to the receptor assay resulted in lower amounts of estimated androgen receptors. A method for routine evaluation of nuclear androgen receptors in prostatic tissue has been evaluated, which involves extraction of nuclear pellets with a heparin-containing (1 g/l) buffer, exchange labelling of the nuclear extracts for 20 h at 100C and quantification of the receptors with protamine sulphate precipitation. (Auth.)

  5. Quantitative assessment of quality of life in New Zealand prostate cancer survivors: the effect of androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Keogh JW

    2013-04-01

    Full Text Available Men with prostate cancer experience many challenges to their quality of life (QOL. While some of these challenges reflect the direct effects of the cancer, additional side-effects and symptoms are also associated with common treatments especially androgen deprivation therapy (ADT. While several studies have examined the effects of ADT on the QOL of men with prostate cancer, much of this research is between 10-20 years old and was conducted in North America or Europe. This study therefore examined the effects of ADT on QOL in prostate cancer patients (survivors in the Southern hemisphere. The registries of two New Zealand based hospitals were sourced to identify men with prostate cancer who were using ADT for at least six months (ADT group, n=205 and those who had never used ADT (non-ADT group, n=143. Participants in both groups were mailed a letter of invitation, the WHOQOL-BREF and three facets of the WHOQOL-OLD QOL questionnaire. Response rates of 41% and 40% were obtained for the ADT and non-ADT groups, respectively. QOL scores were generally similar between the groups, with the exception of physical QOL, which was significantly lower in the ADT group. Such results suggest that cancer clinicians, allied health professionals and cancer researchers should not just concentrate on the physical effect of ADT on their survivors’ risk of developing osteoporosis, falls-related fracture and cardio-metabolic syndrome, but also devote time to ensure their survivors’ perception of their physical QOL is not compromised.

  6. Androgen signaling promotes translation of TMEFF2 in prostate cancer cells via phosphorylation of the α subunit of the translation initiation factor 2.

    Directory of Open Access Journals (Sweden)

    Ryan F Overcash

    Full Text Available The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2, is expressed mainly in brain and prostate. Expression of TMEFF2 is deregulated in prostate cancer, suggesting a role in this disease, but the molecular mechanism(s involved in this effect are not clear. Although androgens promote tmeff2 transcription, androgen delivery to castrated animals carrying CWR22 xenografts increases TMEFF2 protein levels in the absence of mRNA changes, suggesting that TMEFF2 may also be post-transcriptionally regulated. Here we show that translation of TMEFF2 is regulated by androgens. Addition of physiological concentrations of dihydrotestosterone (DHT to prostate cancer cell lines increases translation of endogenous TMEFF2 or transfected TMEFF2-Luciferase fusions, and this effect requires the presence of upstream open reading frames (uORFs in the 5'-untranslated region (5'-UTR of TMEFF2. Using chemical and siRNA inhibition of the androgen receptor (AR, we show that the androgen effect on TMEFF2 translation is mediated by the AR. Importantly, DHT also promotes phosphorylation of the α subunit of the translation initiation factor 2 (eIF2α in an AR-dependent manner, paralleling the effect on TMEFF2 translation. Moreover, endoplasmic reticulum (ER stress conditions, which promote eIF2α phosphorylation, also stimulate TMEFF2 translation. These results indicate that androgen signaling promotes eIF2α phosphorylation and subsequent translation of TMEFF2 via a mechanism that requires uORFs in the 5'-UTR of TMEFF2.

  7. Suppression of rat and human androgen biosynthetic enzymes by apigenin: Possible use for the treatment of prostate cancer.

    Science.gov (United States)

    Wang, Xiudi; Wang, Guimin; Li, Xiaoheng; Liu, Jianpeng; Hong, Tingting; Zhu, Qiqi; Huang, Ping; Ge, Ren-Shan

    2016-06-01

    Apigenin is a natural flavone. It has recently been used as a chemopreventive agent. It may also have some beneficial effects to treat prostate cancer by inhibiting androgen production. The objective of the present study was to investigate the effects of apigenin on the steroidogenesis of rat immature Leydig cells and some human testosterone biosynthetic enzyme activities. Rat immature Leydig cells were incubated for 3h with 100μM apigenin without (basal) or with 1ng/ml luteinizing hormone (LH), 10mM 8-bromoadenosine 3',5'-cyclic monophosphate (8BR), and 20μM of the following steroid substrates: 22R-hydroxychloesterol (22R), pregnenolone (P5), progesterone (P4), and androstenedione (D4). The medium levels of 5α-androstane-3α, 17β-diol (DIOL), the primary androgen produced by rat immature Leydig cells, were measured. Apigenin significantly inhibited basal, 8BR, 22R, PREG, P4, and D4 stimulated DIOL production in rat immature Leydig cells. Further study showed that apigenin inhibited rat 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase/17, 20-lyase, and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 11.41±0.7, 8.98±0.10, and 9.37±0.07μM, respectively. Apigenin inhibited human 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 with IC50 values of 2.17±0.04 and 1.31±0.09μM, respectively. Apigenin is a potent inhibitor of rat and human steroidogenic enzymes, being possible use for the treatment of prostate cancer. PMID:27102611

  8. p300 Acetyltransferase Regulates Androgen Receptor Degradation and PTEN-Deficient Prostate Tumorigenesis

    NARCIS (Netherlands)

    Zhong, J.; Ding, L.; Bohrer, L.R.; Pan, Y.; Liu, P.; Zhang, Jun; Sebo, T.J.; Karnes, R.J.; Tindall, D.J.; Deursen, J.M. van; Huang, H.

    2014-01-01

    Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate

  9. [Radiolabeled androgens and progestins as imaging agents for tumors of the prostate and breast]. Progress report

    Energy Technology Data Exchange (ETDEWEB)

    Katzenellenbogen, J.A.

    1991-12-31

    The specific aims of the previous grant application can be summarized as follows: Synthesize fluorine-substituted progestins from the following high affinity classes: R5020 (promegestone), norgestrel, RU486, and retroprogestins; Synthesize fluorine-substituted androgens from the following high affinity classes: mibolerone, R1881 (metribolone) and 2-oxometribolone; Evaluate the receptor binding and non-specific binding of these fluorosteroids by in vitro binding assays; Develop and optimize fluoride ion substitution reactions suitable for the rapid, efficient and convenient preparation of these fluorosteroids in high specific activity, F-18 labeled form; and Evaluate the target tissue uptake of the F-18 labeled androgens and progestins in experimental animals.

  10. (Radiolabeled androgens and progestins as imaging agents for tumors of the prostate and breast)

    Energy Technology Data Exchange (ETDEWEB)

    Katzenellenbogen, J.A.

    1991-01-01

    The specific aims of the previous grant application can be summarized as follows: Synthesize fluorine-substituted progestins from the following high affinity classes: R5020 (promegestone), norgestrel, RU486, and retroprogestins; Synthesize fluorine-substituted androgens from the following high affinity classes: mibolerone, R1881 (metribolone) and 2-oxometribolone; Evaluate the receptor binding and non-specific binding of these fluorosteroids by in vitro binding assays; Develop and optimize fluoride ion substitution reactions suitable for the rapid, efficient and convenient preparation of these fluorosteroids in high specific activity, F-18 labeled form; and Evaluate the target tissue uptake of the F-18 labeled androgens and progestins in experimental animals.

  11. Reduced Cardiovascular Capacity and Resting Metabolic Rate in Men with Prostate Cancer Undergoing Androgen Deprivation: A Comprehensive Cross-Sectional Investigation

    Directory of Open Access Journals (Sweden)

    Bradley A. Wall

    2015-01-01

    Full Text Available Objectives. To investigate if androgen deprivation therapy exposure is associated with additional risk factors for cardiovascular disease and metabolic treatment-related toxicities. Methods. One hundred and seven men (42–89 years with prostate cancer undergoing androgen deprivation therapy completed a maximal graded objective exercise test to determine maximal oxygen uptake, assessments for resting metabolic rate, body composition, blood pressure and arterial stiffness, and blood biomarker analysis. A cross-sectional analysis was undertaken to investigate the potential impact of therapy exposure with participants stratified into two groups according to duration of androgen deprivation therapy (<3 months and ≥3 months. Results. Maximal oxygen uptake (26.1 ± 6.0 mL/kg/min versus 23.2 ± 5.8 mL/kg/min, p=0.020 and resting metabolic rate (1795 ± 256 kcal/d versus 1647 ± 236 kcal/d, p=0.005 were significantly higher in those with shorter exposure to androgen deprivation. There were no differences between groups for peripheral and central blood pressure, arterial stiffness, or metabolic profile. Conclusion. Three months or longer exposure to androgen deprivation therapy was associated with reduced cardiorespiratory capacity and resting metabolic rate, but not in a range of blood biomarkers. These findings suggest that prolonged exposure to androgen deprivation therapy is associated with negative alterations in cardiovascular outcomes. Trial registry is: ACTRN12609000200280.

  12. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling.

    Science.gov (United States)

    Nguyen, Holly M; Ruppender, Nazanin; Zhang, Xiaotun; Brown, Lisha G; Gross, Ted S; Morrissey, Colm; Gulati, Roman; Vessella, Robert L; Schimmoller, Frauke; Aftab, Dana T; Corey, Eva

    2013-01-01

    Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease. PMID:24205338

  13. Cabozantinib inhibits growth of androgen-sensitive and castration-resistant prostate cancer and affects bone remodeling.

    Directory of Open Access Journals (Sweden)

    Holly M Nguyen

    Full Text Available Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa, cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease.

  14. Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer

    Science.gov (United States)

    Pinto, Filipe; Pértega-Gomes, Nelma; Vizcaíno, José R.; Andrade, Raquel P.; Cárcano, Flavio M.; Reis, Rui Manuel

    2016-01-01

    Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD). Recently, we identified Brachyury as a new biomarker of PCa aggressiveness and poor prognosis. In the present study we aimed to assess the role of Brachyury in PCa therapy resistance. We showed that Brachyury overexpression in prostate cancer cells lines increased resistance to docetaxel and cabazitaxel drugs, whereas Brachyury abrogation induced decrease in therapy resistance. Through ChiP-qPCR assays we further demonstrated that Brachyury is a direct regulator of AR expression as well as of the biomarker AMACR and the mesenchymal markers Snail and Fibronectin. Furthermore, in vitro Brachyury was also able to increase EMT and stem properties. By in silico analysis, clinically human Brachyury-positive PCa samples were associated with biomarkers of PCa aggressiveness and therapy resistance, including PTEN loss, and expression of NEtD markers, ERG and Bcl-2. Taken together, our results indicate that Brachyury contributes to tumor chemotherapy resistance, constituting an attractive target for advanced PCa patients. PMID:27049720

  15. Combination of carmustine and selenite effectively inhibits tumor growth by targeting androgen receptor, androgen receptor-variants, and Akt in preclinical models: New hope for patients with castration resistant prostate cancer.

    Science.gov (United States)

    Thamilselvan, Vijayalakshmi; Menon, Mani; Thamilselvan, Sivagnanam

    2016-10-01

    Despite established androgen receptor (AR) antagonists, AR/AR-variants signaling remain a major obstacle for the successful treatment of castration resistant prostate cancer (CRPC). In addition, CRPC cells adapt to survive via AR-independent pathways to escape next generation therapies. Therefore, there is an urgent need for drugs that can target these signaling pathways in CRPC. In this study, we sought to determine whether carmustine and selenite in combination could induce apoptosis and inhibit growth of CRPC in-vitro and in-vivo. CRPC (22Rv1, VCaP, and PC-3) cell lines in culture and xenograft mouse were used. Combination of carmustine and selenite treatment significantly increased reactive oxygen species, apoptosis and growth inhibition in CRPC cells with down regulation of anti-apoptotic (Bcl-2 and Mcl-1) and proliferative proteins (c-Myc and cyclin-D1). This effect was associated with complete reduction of AR/AR-variants, AR-V7, PSA and significant induction of p27Kip1. Combination treatment substantially abolished phospho-Akt, phospho-GSK-3β, and anchorage-independent growth in AR-positive and AR-negative cells. Consistent with in-vitro results, combination treatment effectively induced apoptosis and completely inhibited xenograft tumor growth and markedly reduced AR/AR-variants, AR-V7, PSA, and Bcl-2 in xenograft tumors without causing genotoxicity in host mice. Individual agent treatment showed only partial effect. The combination treatment showed a significant synergistic effect. The present study is the first to demonstrate that the combination of carmustine and selenite treatment completely suppressed CRPC tumor growth by reducing AR/AR-variants and Akt signaling. Our findings suggest that the combination of carmustine and selenite could constitute a promising next-generation therapy for successful treatment of patients with CRPC. PMID:27198552

  16. Radiation dose escalation or longer androgen suppression for locally advanced prostate cancer? Data from the TROG 03.04 RADAR trial

    International Nuclear Information System (INIS)

    Background: The relative effects of radiation dose escalation (RDE) and androgen suppression (AS) duration on local prostatic progression (LP) remain unclear. Methods: We addressed this in the TROG 03.04 RADAR trial by incorporating a RDE programme by stratification at randomisation. Men were allocated 6 or 18 months AS ± 18 months zoledronate (Z). The main endpoint was a composite of clinically diagnosed LP or PSA progression with a PSA doubling time ⩾6 months. Fine and Gray competing risk modelling with adjustment for site clustering produced cumulative incidence estimates at 6.5 years for each RDE group. Results: Composite LP declined coherently in the 66, 70 and 74 Gy external beam dosing groups and was lowest in the high dose rate brachytherapy boost (HDRB) group. At 6.5 years, adjusted cumulative incidences were 22%, 15%, 13% and 7% respectively. Compared to 6 months AS, 18 months AS also significantly reduced LP (p < 0.001). Post-radiation urethral strictures were documented in 45 subjects and increased incrementally in the dosing groups. Crude incidences were 0.8%, 0.9%, 3.8% and 12.7% respectively. Conclusion: RDE and increasing AS independently reduce LP and increase urethral strictures. The risks and benefits to the individual must be balanced when selecting radiation dose and AS duration

  17. Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime

    International Nuclear Information System (INIS)

    Purpose: High-dose radiotherapy, delivered in an accelerated hypofractionated course, was utilized to treat prostate cancer. Therapy consisted of external beam radiotherapy (EBRT) and transrectal ultrasound (TRUS)-guided conformally modulated high-dose rate (HDR) brachytherapy. The purpose of this report is (1) to assess long-term comparative outcomes from three trials using similar accelerated hypofractionated regimes; and (2) to examine the long-term survival impact of a short course of ≤6 months adjuvant/concurrent androgen deprivation when a very high radiation dose was delivered. Methods and Materials: Between 1986 and 2000, 1,260 patients were treated at three institutions with pelvic EBRT (36-50 Gy) integrated with HDR prostate brachytherapy. The total dose including brachytherapy was given over 5 weeks. The biologic equivalent EBRT dose ranged between 90 and 123 Gy (median, 102 Gy) using an α /β of 1.2. Patient eligibility criteria included a pretreatment prostate-specific antigen ≥10, Gleason score ≥7, or clinical stage ≥T2b. A total of 1,260 patients were treated, and 934 meet the criteria. Kiel University Hospital treated 198 patients; William Beaumont Hospital, 315; and California Endocurietherapy Cancer Center, 459 patients. Brachytherapy dose regimes were somewhat different between centers and the dose was escalated from 5.5 x 3 to 15 Gy x 2 Gy. Patients were divided for analysis between the 406 who received up to 6 months of androgen deprivation therapy and the 528 patients who did not. All patients had a minimum follow-up of 18 months (3 times the exposure to androgen deprivation therapy). The American Society for Therapeutic Radiology and Oncology biochemical failure definition was used. Results: Mean age was 69 years. Median follow-up time was 4.4 years (range, 1.5-14.5); 4 years for androgen deprivation therapy patients and 4.9 for radiation alone. There was no difference at 5 and 8 years in overall survival, cause-specific survival, or

  18. Diabetes protects from prostate cancer by downregulating androgen receptor: new insights from LNCaP cells and PAC120 mouse model.

    Directory of Open Access Journals (Sweden)

    Anna Barbosa-Desongles

    Full Text Available Type 2 diabetes has been associated with decreased risk of prostate cancer in observational studies, and this inverse association has been recently confirmed in several large cohort studies. However the mechanisms involved in this protective effect remain to be elucidated. The aim of the present study was to explore whether different features of type 2 diabetes (hyperinsulinemia, hyperglycemia and tumor necrosis factor alpha [TNF-α] protect against the development of prostate cancer. For this purpose LNCaP cells were used for in vitro experiments and nude mice in which PAC120 (hormone-dependent human prostate cancer xenografts had been implanted were used for in vivo examinations. We provide evidence that increasing glucose concentrations downregulate androgen receptor (AR mRNA and protein levels through NF-κB activation in LNCaP cells. Moreover, there was a synergic effect of glucose and TNFα in downregulating the AR in LNCaP cells. By contrast, insulin had no effect on AR regulation. In vivo experiments showed that streptozotocin-induced diabetes (STZ-DM produces tumor growth retardation and a significant reduction in AR expression in PAC120 prostate cancer mice. In conclusion, our results suggest that hyperglycemia and TNF-α play an important role in protecting against prostate cancer by reducing androgen receptor levels via NF-κB.

  19. Metabolism of adrenal androgen and its impacts on prostate cancer after castration

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    @@ With the extensive utilization of PSA,digital rectum examination and transrectal ultrasound for screening in the aging population,the diagnosis of prostate cancer in China has markedly increased during the past years,particularly in developed regions.

  20. Biochemical Response to Androgen Deprivation Therapy Before External Beam Radiation Therapy Predicts Long-term Prostate Cancer Survival Outcomes

    Energy Technology Data Exchange (ETDEWEB)

    Zelefsky, Michael J., E-mail: zelefskm@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Gomez, Daniel R.; Polkinghorn, William R.; Pei, Xin; Kollmeier, Marisa [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2013-07-01

    Purpose: To determine whether the response to neoadjuvant androgen deprivation therapy (ADT) defined by a decline in prostate-specific antigen (PSA) to nadir values is associated with improved survival outcomes after external beam radiation therapy (EBRT) for prostate cancer. Methods and Materials: One thousand forty-five patients with localized prostate cancer were treated with definitive EBRT in conjunction with neoadjuvant and concurrent ADT. A 6-month course of ADT was used (3 months during the neoadjuvant phase and 2 to 3 months concurrently with EBRT). The median EBRT prescription dose was 81 Gy using a conformal-based technique. The median follow-up time was 8.5 years. Results: The 10-year PSA relapse-free survival outcome among patients with pre-radiation therapy PSA nadirs of ≤0.3 ng/mL was 74.3%, compared with 57.7% for patients with higher PSA nadir values (P<.001). The 10-year distant metastases-free survival outcome among patients with pre-radiation therapy PSA nadirs of ≤0.3 ng/mL was 86.1%, compared with 78.6% for patients with higher PSA nadir values (P=.004). In a competing-risk analysis, prostate cancer-related deaths were also significantly reduced among patients with pre-radiation therapy PSA nadirs of <0.3 ng/mL compared with higher values (7.8% compared with 13.7%; P=.009). Multivariable analysis demonstrated that the pre-EBRT PSA nadir value was a significant predictor of long-term biochemical tumor control, distant metastases-free survival, and cause-specific survival outcomes. Conclusions: Pre-radiation therapy nadir PSA values of ≤0.3 ng/mL after neoadjuvant ADT were associated with improved long-term biochemical tumor control, reduction in distant metastases, and prostate cancer-related death. Patients with higher nadir values may require alternative adjuvant therapies to improve outcomes.

  1. Prognostic Significance of PSA, Gleason Score, Bone Metastases in Patients with Metastatic Prostate Cancer Under Palliative Androgen Deprivation Treatment

    International Nuclear Information System (INIS)

    Objective: The aim of this study was to evaluate the prognostic significance of each of the following in the development and progression of hormonal refractory disease in patients with metastatic prostate cancer under hormonal palliative treatment: The initial serum level prostate specific antigen (PSA), the Gleason score (GS), the presence of bone metastases with or without visceral metastases, and the PSA decline. Patients and Methods: During the time period from January 2005 to December 2008, a total of 92 patients with newly diagnosed, histologically confirmed metastatic prostate cancer (MPC) were under palliative androgen deprivation therapy. The age range was 52 to 85 years with a mean age of 66.2±7.9 years. MPC was diagnosed histologically after transrectal ultrasonography guided biopsy. The Gleason score assessment was determined by low power microscopic examination. Metastases were confirmed by positive bone scintigraphy with 925 MBq 99mTc-MDP using a tomographic gamma camera, computerized axial tomography or magnetic resonance imagining. Measurements of PSA levels were conducted by the radioimmunoassay method. The influences of the following prognostic factors were evaluated: The initial serum level of prostate specific antigen (PSA), the Gleason score (GS), the presence of bone metastases with or without visceral metastases, and the PSA decline, on the time to disease progression. Results: The time to progression was significantly delayed in patients with initial PSA level £50 ng/ml (median: 32 months), Gleason Score £7 (median: 33 months), bone metastases only (median: 30 months) and PSA level normalization within 6 months (median: 30 months) compared to that of patients with initial PSA level >50 ng/ml (median: 24 months), Gleason Score >7 (median: 24 months), bone, distant lymph nodes and/or visceral metastases (median: 24 months), PSA level decline (median: 18 months) (p-values were 0.002, 6 sites bone metastases (median: 28 months) (p=0

  2. Recognizing False Biochemical Failure Calls After Radiation With or Without Neo-Adjuvant Androgen Deprivation for Prostate Cancer

    International Nuclear Information System (INIS)

    Purpose: We studied prostate-specific antigen (PSA) changes after radiation with or without neoadjuvant androgen deprivation to determine posttreatment PSA scenarios in which false-positive biochemical failures (FPBF) are most likely to occur. Methods and Materials: In the Trans-Tasman Radiation Oncology 96.01 Group trial, patients with T2b, 2c, 3, 4 N0 prostate cancer were randomized to 3 or 6 months goserelin and flutamide (STAD) before and during 66 Gy to the prostate and seminal vesicles (XRT) or to XRT alone. Piecewise longitudinal changes in PSA before relapse were characterized and quantified to determine which might cause FPBF calls. Results: Between 1996 and 2000, 802 eligible patients were randomized. Of these, 492 met the criteria for American Society for Therapeutic Radiology and Oncology (ASTRO) failure and 467 for Phoenix failure. Seventy-seven ASTRO fails and 39 Phoenix fails were deemed false positives (FPs). The majority of FPBFs were associated with the 'plateauing' in PSA values that follow posttreatment nadir. FPBFs were particularly common in men treated with STAD, in whom small, consecutive PSA rises before or during this phenomenon triggered 56 FP ASTRO fail calls. In these men, the Phoenix fail criteria triggered only 15 FPBF calls. However, the Phoenix criteria were more vulnerable than ASTRO to short-term isolated PSA rises during plateau, which resulted in 15 Phoenix fail calls but only 3 FP ASTRO fails. Conclusions: The Phoenix definition avoided 50% of FPBF calls that occurred with the ASTRO definition. Failures should be confirmed by further PSA rises before investigation and treatment is considered.

  3. Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives

    Directory of Open Access Journals (Sweden)

    Saleh A. Bahashwan

    2014-11-01

    Full Text Available A series of substituted pyrazole, triazole and thiazole derivatives (2–13 were synthesized from 1-(naphtho[1,2-d]thiazol-2-ylhydrazine as starting material and evaluated as androgen receptor antagonists and anti-prostate cancer agents. The newly synthesized compounds showed potent androgen receptor antagonists and anti-prostate cancer activities with low toxicity (lethal dose 50 (LD50 comparable to Bicalutamide as reference drug. The structures of newly synthesized compounds were confirmed by IR, 1H-NMR, 13C-NMR, and MS spectral data and elemental analysis. The detailed synthesis, spectroscopic data, LD50 values and pharmacological activities of the synthesized compounds are reported.

  4. Androgen Receptor Antagonists and Anti-Prostate Cancer Activities of Some Newly Synthesized Substituted Fused Pyrazolo-, Triazolo- and Thiazolo-Pyrimidine Derivatives

    Science.gov (United States)

    Bahashwan, Saleh A.; Fayed, Ahmed A.; Ramadan, Mohamed A.; Amr, Abd El-Galil E.; Al-Harbi, Naif O.

    2014-01-01

    A series of substituted pyrazole, triazole and thiazole derivatives (2–13) were synthesized from 1-(naphtho[1,2-d]thiazol-2-yl)hydrazine as starting material and evaluated as androgen receptor antagonists and anti-prostate cancer agents. The newly synthesized compounds showed potent androgen receptor antagonists and anti-prostate cancer activities with low toxicity (lethal dose 50 (LD50)) comparable to Bicalutamide as reference drug. The structures of newly synthesized compounds were confirmed by IR, 1H-NMR, 13C-NMR, and MS spectral data and elemental analysis. The detailed synthesis, spectroscopic data, LD50 values and pharmacological activities of the synthesized compounds are reported. PMID:25421248

  5. Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model

    Directory of Open Access Journals (Sweden)

    Chang Chin-Pao

    2011-01-01

    Full Text Available Abstract Background Hedgehog signalling has been implicated in prostate tumorigenesis in human subjects and mouse models, but its effects on transforming normal basal/stem cells toward malignant cancer stem cells remain poorly understood. Methods We produced pCX-shh-IG mice that overexpress Hedgehog protein persistently in adult prostates, allowing for elucidation of the mechanism during prostate cancer initiation and progression. Various markers were used to characterize and confirm the transformation of normal prostate basal/stem cells into malignant cancer stem cells under the influence of Hedgehog overexpression. Results The pCX-shh-IG mice developed prostatic intraepithelial neoplasia (PIN that led to invasive and metastatic prostate cancers within 90 days. The prostate cancer was initiated through activation of P63+ basal/stem cells along with simultaneous activation of Hedgehog signalling members, suggesting that P63+/Patch1+ and P63+/Smo+ cells may serve as cancer-initiating cells and progress into malignant prostate cancer stem cells (PCSCs. In the hyperplastic lesions and tumors, the progeny of PCSCs differentiated into cells of basal-intermediate and intermediate-luminal characteristics, whereas rare ChgA+ neuroendocrine differentiation was seen. Furthermore, in the metastatic loci within lymph nodes, kidneys, and lungs, the P63+ PCSCs formed prostate-like glandular structures, characteristic of the primitive structures during early prostate development. Besides, androgen receptor (AR expression was detected heterogeneously during tumor progression. The existence of P63+/AR-, CK14+/AR- and CD44+/AR- progeny indicates direct procurement of AR- malignant cancer trait. Conclusions These data support a cancer stem cell scenario in which Hedgehog signalling plays important roles in transforming normal prostate basal/stem cells into PCSCs and in the progression of PCSCs into metastatic tumor cells.

  6. A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design

    International Nuclear Information System (INIS)

    Studies indicate that strength training has beneficial effects on clinical health outcomes in prostate cancer patients during androgen deprivation therapy. However, randomized controlled trials are needed to scientifically determine the effectiveness of strength training on the muscle cell level. Furthermore, close examination of the feasibility of a high-load strength training program is warranted. The Physical Exercise and Prostate Cancer (PEPC) trial is designed to determine the effectiveness of strength training on clinical and muscle cellular outcomes in non-metastatic prostate cancer patients after high-dose radiotherapy and during ongoing androgen deprivation therapy. Patients receiving androgen deprivation therapy for 9-36 months combined with external high-dose radiotherapy for locally advanced prostate cancer are randomized to an exercise intervention group that receives a 16 week high-load strength training program or a control group that is encouraged to maintain their habitual activity level. In both arms, androgen deprivation therapy is continued until the end of the intervention period. Clinical outcomes are body composition (lean body mass, bone mineral density and fat mass) measured by Dual-energy X-ray Absorptiometry, serological outcomes, physical functioning (muscle strength and cardio-respiratory fitness) assessed with physical tests and psycho-social functioning (mental health, fatigue and health-related quality of life) assessed by questionnaires. Muscle cellular outcomes are a) muscle fiber size b) regulators of muscle fiber size (number of myonuclei per muscle fiber, number of satellite cells per muscle fiber, number of satellite cells and myonuclei positive for androgen receptors and proteins involved in muscle protein degradation and muscle hypertrophy) and c) regulators of muscle fiber function such as proteins involved in cellular stress and mitochondrial function. Muscle cellular outcomes are measured on muscle cross sections and

  7. Indole-3-carbinol and 3’, 3’-diindolylmethane modulate androgen effect up-regulation on C-C chemokine ligand 2 and monocyte attraction to prostate cancer cells

    Science.gov (United States)

    Inflammation has a role in prostate tumorigenesis. Recruitment of inflammatory monocytes to the tumor site is mediated by C-C chemokine ligand 2 (CCL2) through binding to its receptor CCR2. We hypothesized that androgen could modulate CCL2 expression in hormone-responsive prostate cancer cells, and ...

  8. A phase II RCT and economic analysis of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy

    OpenAIRE

    Alibhai, Shabbir MH; Santa Mina, Daniel; Ritvo, Paul; Sabiston, Catherine; Krahn, Murray; Tomlinson, George; Matthew, Andrew; Segal, Roanne; Warde, Padraig; Durbano, Sara; O’Neill, Meagan; Culos-Reed, Nicole

    2015-01-01

    Background Androgen deprivation therapy is commonly used to treat prostate cancer, the most common visceral cancer in men. However, various side effects often worsen physical functioning and reduce well-being among men on this treatment. Based on existing evidence, both resistance and aerobic training provide benefits for this population yet adherence rates are often low. The method of exercise delivery (supervised in-center or home-based) may be important, yet few studies have compared diffe...

  9. Repression of Runx2 by Androgen Receptor (AR) in Osteoblasts and Prostate Cancer Cells: AR Binds Runx2 and Abrogates Its Recruitment to DNA

    OpenAIRE

    Baniwal, Sanjeev K.; Khalid, Omar; Sir, Donna; Buchanan, Grant; Coetzee, Gerhard A.; Frenkel, Baruch

    2009-01-01

    Runx2 and androgen receptor (AR) are master transcription factors with pivotal roles in bone metabolism and prostate cancer (PCa). We dissected AR-mediated repression of Runx2 in dihydrotestosterone (DHT)-treated osteoblastic and PCa cells using reporter assays and endogenous Runx2 target genes. Repression required DHT, but not AR’s transactivation function, and was associated with nuclear colocalization of the two proteins. Runx2 and AR coimmunoprecipitated and interacted directly in glutath...

  10. Development of a Nomogram Model Predicting Current Bone Scan Positivity in Patients Treated with Androgen-Deprivation Therapy for Prostate Cancer

    OpenAIRE

    Gotto, Geoffrey T.; Yu, Changhong; Bernstein, Melanie; Eastham, James A.; Michael W Kattan

    2014-01-01

    Purpose: To develop a nomogram predictive of current bone scan positivity in patients receiving androgen-deprivation therapy (ADT) for advanced prostate cancer; to augment clinical judgment and highlight patients in need of additional imaging investigations. Materials and methods: A retrospective chart review of bone scan records (conventional 99mTc-scintigraphy) of 1,293 patients who received ADT at the Memorial Sloan-Kettering Cancer Center from 2000 to 2011. Multivariable logistic regre...

  11. Feasibility study of a randomised controlled trial to compare (deferred) androgen deprivation therapy and cryotherapy in men with localised radiation-recurrent prostate cancer

    OpenAIRE

    Salji, M; Jones, R; Paul, J.; Birrell, F.; Dixon-Hughes, J; Hutchison, C; Johansen, T E B; Greene, D.; Parr, N; Leung, H Y

    2014-01-01

    Background: Salvage therapeutic options for biochemical failure after primary radiation-based therapy include radical prostatectomy, cryoablation, high-intensity focused ultrasound (HIFU), brachytherapy (for post-EBRT patients) and androgen deprivation therapy (ADT). ADT and salvage prostate cryoablation (SPC) are two commonly considered treatment options for RRPC. However, there is an urgent need for high-quality clinical studies to support evidence-based decisions on treatment choice. Our s...

  12. Phase II Study of Dutasteride for Recurrent Prostate Cancer During Androgen Deprivation Therapy

    Science.gov (United States)

    Shah, Satyan K.; Trump, Donald L.; Sartor, Oliver; Tan, Wei; Wilding, Gregory E.; Mohler, James L.

    2010-01-01

    Purpose We determined the response rate to and safety of a dual 5α-reductase inhibitor, dutasteride, in men with castration recurrent prostate cancer. Materials and Methods A total of 28 men with asymptomatic castration recurrent prostate cancer were treated with 3.5 mg dutasteride daily (luteinizing hormone-releasing hormone treatment continued), and evaluated monthly for response and toxicity. Eligibility included appropriate duration antiandrogen withdrawal, baseline prostate specific antigen 2.0 ng/ml or greater and a new lesion on bone scan, increase in measurable disease using Response Evaluation Criteria in Solid Tumors criteria, or 2 or more consecutive prostate specific antigen measurements increased over baseline. Outcomes were progression, stable disease, partial response (prostate specific antigen less than 50% of enrollment for 4 or more weeks) or complete response. Results There were 25 evaluable men with a mean age of 70 years (range 57 to 88), a mean prostate specific antigen of 61.9 ng/ml (range 5.0 to 488.9) and mean Gleason score 8 (range 6 to 10), 15 of whom had bone metastases. Eight men had 10 grade 3 or higher adverse events using National Cancer Institute Common Terminology Criteria, all of which were judged to be unrelated to treatment. Of the 25 men 14 had disease progression by 2 months, 9 had stable (2.5, 3, 3, 4, 4, 5, 5, 8.5, 9 months) disease, 2 had a partial response and none had a complete response. Overall median time to progression was 1.87 months (range 1 to 10, 95% CI 1.15–3.91). Conclusions Dutasteride rarely produces biochemical responses in men with castration recurrent prostate cancer. However, further study is warranted given its favorable safety profile. PMID:19091347

  13. Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

    International Nuclear Information System (INIS)

    Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily

  14. Sunitinib Plus Androgen Deprivation and Radiation Therapy for Patients With Localized High-Risk Prostate Cancer: Results From a Multi-institutional Phase 1 Study

    Energy Technology Data Exchange (ETDEWEB)

    Corn, Paul G., E-mail: pcorn@mdanderson.org [Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Song, Danny Y. [Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland (United States); Heath, Elisabeth; Maier, Jordan [Karmanos Cancer Institute, Wayne State University, Detroit, Michigan (United States); Meyn, Raymond [Department of Experimental Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); Kuban, Deborah [Department of Radiation Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States); DePetrillo, Thomas A. [Department of Radiation Oncology, Tufts Medical Center, Boston, Massachusetts (United States); Mathew, Paul, E-mail: pmathew@tuftsmedicalcenter.org [Department of Hematology-Oncology, Tufts Medical Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas (United States)

    2013-07-01

    Purpose: To evaluate the feasibility of administering sunitinib in combination with androgen deprivation therapy and external-beam intensity modulated radiation therapy (XRT) in patients with localized high-risk prostate cancer. Methods and Materials: Seventeen men with localized adenocarcinoma of the prostate with cT2c-cT4 or Gleason 8-10 or prostate-specific antigen >20 ng/mL received initial androgen deprivation (leuprolide 22.5 mg every 12 weeks plus oral bicalutamide 50 mg daily) for 4-8 weeks before oral sunitinib 12.5, 25, or 37.5 mg daily for 4 weeks as lead-in, then concurrently with and 4 weeks after XRT (75.6 Gy in 42 fractions to prostate and seminal vesicles). A 3+3 sequential dose-escalation design was used to assess the frequency of dose-limiting toxicity (DLT) and establish a maximal tolerated dose of sunitinib. Results: Sunitinib at 12.5- and 25-mg dose levels was well tolerated. The first 4 patients enrolled at 37.5 mg experienced a DLT during lead-in, and a drug interaction between sunitinib and bicalutamide was suspected. The protocol was revised and concurrent bicalutamide omitted. Of the next 3 patients enrolled at 37.5 mg, 2 of 3 receiving concurrent therapy experienced DLTs during radiation: grade 3 diarrhea and grade 3 proctitis, respectively. Only 1 of 7 patients completed sunitinib at 37.5 mg daily, whereas 3 of 3 patients (25 mg as starting dose) and 3 of 4 patients (25 mg as reduced dose) completed therapy. Conclusions: The feasibility of combined vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitor therapy, androgen deprivation, and radiation therapy for prostate cancer was established. Using a daily dosing regimen with lead-in, concurrent, and post-XRT therapy, the recommended phase 2 dose of sunitinib is 25 mg daily.

  15. Biological aspects of the potential interaction between androgen suppression and radiation therapy

    International Nuclear Information System (INIS)

    It is a basic axiom of radiotherapy that the radiation dose required for tumor eradication increases with increasing tumor volume. These Patterns of Care Studies and prospective studies using rebiopsy have shown that this holds true for prostate cancer as well. Despite our best endeavors with conventional dose, there remains a substantial element of local failure following radiotherapy, and this is T-stage related. Unlikely many other solid tumors, a convenient method of volume reduction exists for prostate carcinoma. Approximately 90% demonstrate shrinkage following androgen suppression, an effect that is more pronounced at the primary site than metastatic sites. Transrectal ultrasound studies have shown a median of 40% prostatic tumor volume reduction after 3-4 months of androgen suppression. With more protracted androgen suppression the shrinkage progresses and a small minority of patients may actually have a complete response determined pathologically. Animal models demonstrate clearly that the TCD50 of androgen dependent tumors may be decreased by prior androgen depression. This effect is most pronounced if radiation is deferred until the time of maximal tumor regression. The advantage is lost if the tumor is allowed to regrow in an androgen independent fashion to its original volume. It is not clear whether this benefit of neoadjuvant androgen suppression results solely from volume shrinkage. The potential for synergy exists as both radiation and androgen suppression have an element of apoptosis as a common pathway of cell death. Although apoptosis is certainly the major cause of cell death from androgen suppression its' contribution to radiation cell kill in prostatic adenocarcinomas is yet to be evaluated. If the two effects are additive and not synergistic, then sequence should be unimportant. Animal models, however, demonstrate that the TCD50 of androgen dependent tumors is not significantly reduced by adjuvant androgen suppression. Human data is still

  16. Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

    International Nuclear Information System (INIS)

    Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12–0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20–0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02–0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0–0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

  17. Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?

    Energy Technology Data Exchange (ETDEWEB)

    Arruda Viani, Gustavo, E-mail: gusviani@gmail.com [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil); Bernardes da Silva, Lucas Godoi; Stefano, Eduardo Jose [Department of Radiation Oncology, Marilia Medical School, Marilia, Sao Paulo (Brazil)

    2012-07-15

    Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N = 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis.

  18. Cardiometabolic complications after androgen deprivation therapy in a man with prostate cancer: effects of three years intermittent testosterone supplementation

    Directory of Open Access Journals (Sweden)

    Antonio eAversa

    2012-02-01

    Full Text Available Androgen deprivation therapy (ADT for prostate carcinoma (PCa may cause cardiometabolic complications unless intermittent androgen blockade (IAB is instituted. An 80-year-old man was diagnosed intermediate grade (Gleason 4+3 PCa and was treated with continuous ADT with triptorelin plus bicalutamide. After 6 months of treatment, he experienced an acute myocardial infarction and one month after hospitalization he came to our outpatient clinic for fatigue, weight gain and hyperglycemia. Due to iatrogenic hypogonadism, we decided to proceed with IAB, but after three months ADT withdrawal his serum testosterone (T was still 0.5 ng/mL. Due to very low concomitant PSA levels (0.1 ng/mL he was then proposed intermittent T-gel supplementation (Tostrex® which was initiated according to the following scheme: 6 months on and three months off. T-gel dose was titrated tri-weekly in order to achieve T plasma levels below 3.49 ng/mL. After six months on, his serum T raised to a mean value of 2.0 ng/mL without increments in PSA. After overall twelve months on, his serum T peaked to a mean value of 3.0 ng/mL while a delay in PSA rise was seen after 24 mo (0.6 ng/mL but remained stable until the last observation carried forward (LOCF, at 45 months. No clinical and biochemical PCa progression were observed at LOCF. Reversion of iatrogenic metabolic syndrome started after six mo of T supplementation without using any add-on treatment. This case provides support that once regression of PCa growth is attained, T supplementation may be administered in well differentiated PCa, especially if IAB is not successful in reverting iatrogenic hypogonadism and its associated cardiac and metabolic complications.

  19. The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy

    DEFF Research Database (Denmark)

    Berg, Kasper Drimer; Røder, Martin A; Thomsen, Frederik B;

    2015-01-01

    BACKGROUND: Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. METHODS: In total, 194 patients with advanced and...... in secondary endpoints were observed. CONCLUSIONS: ERG expression was not associated with risk of CRPC suggesting that ERG is not a candidate biomarker for predicting response to primary ADT in patients diagnosed with advanced and/or metastatic PCa....

  20. Treatment of Prostate Cancer using Anti-androgen Small Molecules | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    The National Cancer Institute seeks parties interested in collaborative research to co-develop and commercialize a new class of small molecules for the treatment of prostate cancer. General information on co-development research collaborations, can be found on our web site (http://ttc.nci.nih.gov/forms).

  1. Effect of androgen deprivation on the expression of aquaporins in rat prostate and seminal vesicles.

    Science.gov (United States)

    Tian, J C; Xia, J Y; Jiang, J; Jiang, R; He, Y Z; Lin, H

    2016-04-01

    The aim of this study was to investigate the level of secretions of prostate and seminal vesicles and its association with the expression of AQP0, 1, 4, 5, 6 and 8 in castrated rats. Eight-week-old male Sprague-Dawley (SD) rats (n = 18) were randomly divided into control group, castrated rats group and castrated followed testosterone replacement group. Four weeks after surgery, the secretions and expression of AQP0, 1, 4, 5, 6 and 8 of prostate and seminal vesicles were determined. Serum testosterone was significantly lower in castrated groups than in control and testosterone replacement groups (P seminal vesicle secretions and the expressions of AQP0, 1, 4, 5, 6 and 8 in prostate and seminal vesicles were significantly lower in castrated group than in control and castrated followed testosterone replacement groups (P seminal vesicle secretions in castrated rats may be related to the decrease in AQP0, 1, 4, 5, 6 and 8 in prostatic tissue and seminal vesicles.

  2. Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy

    International Nuclear Information System (INIS)

    Nomograms were established to predict biochemical recurrence (BCR) after radiotherapy (RT) with a low weight of the characteristic variables of RT and androgen deprivation therapy (ADT). Our aim is to provide a new stratified tool for predicting BCR at 4 and 7 years in patients treated using RT with radical intent. A retrospective, nonrandomized analysis was performed on 5044 prostate cancer (PCa) patients with median age 70 years, who received RT - with or without ADT - between November 1992 and May 2007. Median follow-up was 5.5 years. BCR was defined as a rise in serum prostate-specific antigen (PSA) of 2 ng/ml over the post-treatment PSA nadir. Univariate association between predictor variables and BCR was assessed by the log-rank test, and three linked nomograms were created for multivariate prognosis of BCR-free survival. Each nomogram corresponds to a category of the Gleason score - either 6,7, or 8-10 - and all of them were created from a single proportional hazards regression model stratified also by months of ADT (0, 1-6, 7-12, 13-24, 25-36, 36-60). The performance of this model was analyzed by calibration, discrimination, and clinical utility. Initial PSA, clinical stage, and RT dose were significant variables (p < 0.01). The model showed a good calibration. The concordance probability was 0.779, improving those obtained with other nomograms (0.587, 0.571, 0.554) in the database. Survival curves showed best clinical utility in a comparison with National Comprehensive Cancer Network (NCCN) risk groups. For each Gleason score category, the nomogram provides information on the benefit of adding ADT to a specific RT dose. (orig.)

  3. Clamp ablation of the testes compared to bilateral orchiectomy as androgen deprivation therapy for advanced prostate cancer

    Directory of Open Access Journals (Sweden)

    AD Zarrabi

    2011-06-01

    Full Text Available PURPOSE: Burdizzo clamp ablation of the testes (CAT may provide an incisionless, cost-effective form of androgen deprivation therapy (ADT in men with adenocarcinoma of the prostate (ACP who find bilateral orchiectomy (BO unacceptable or can not afford medical ADT. The aim of this study was to compare CAT with BO as primary ADT in men with ACP. MATERIALS AND METHODS: Written, informed consent was obtained from men with locally advanced or metastatic ACP. Patients were prospectively randomized to BO (n = 9 or CAT (n = 10 under local anaesthesia, and were evaluated 3 and 7 days, 6 weeks and 3 months post-procedure. The protocol was approved by the local institutional ethics committee. Statistical analysis was performed using Student's, Mann-Whitney's and Fisher's tests. RESULTS: Mean duration of the procedure was significantly longer for BO than CAT (16.9 vs. 10.9 minutes. Mean pain scores during and after the procedure did not differ significantly. Serum testosterone decreased significantly on days 3 and 7 after CAT, but increased at 6 weeks, and was significantly higher than after BO. Serum luteinizing hormone increased significantly from day 3 after BO and from day 7 after CAT. Serum prostate specific antigen decreased significantly after BO, but not after CAT. Minor complications were more common after BO (89% than CAT (40%. In the 9 men who did not achieve castrate levels of testosterone after CAT, BO was performed. CONCLUSIONS: CAT was quicker to perform and had a lower complication rate, but was not as effective as BO in achieving castrate serum testosterone levels.

  4. Capsaicin causes inactivation and degradation of the androgen receptor by inducing the restoration of miR-449a in prostate cancer.

    Science.gov (United States)

    Zheng, Long; Chen, Jiaqi; Ma, Zhenkun; Liu, Wei; Yang, Fei; Yang, Zhao; Wang, Ke; Wang, Xinyang; He, Dalin; Li, Lei

    2015-08-01

    Capsaicin, a novel antitumor agent extracted from chili peppers, has been proven to induce growth inhibition in various types of cancer including prostate cancer. However, the detailed mechanisms remain largely undiscovered. In the present study, we explored the regulation of the androgen receptor (AR) by capsaicin and further researched the mechanisms of their interaction in AR-positive prostate cancer cells. In the present study, cell viability was assessed by MTT assay. Cell cycle distribution was determined using flow cytometry. Expression levels of cyclin D1, miR-449a, AR and prostate-specific antigen (PSA) were assessed by quantitative real-time polymerase chain reaction or western blot analysis. To further confirm the relationship among miR-449a, AR and prostate cancer proliferation, miR-449a was overexpressed by a lentivirus in prostate cancer cells. We discovered that capsaicin prevented tumor proliferation and cell cycle progression through inactivation and degradation of AR. We also found that restoration of miR-449a induced by capsaicin treatment resulted in the inhibition of AR signaling. Finally, we demonstrated that increased expression of miR-449a sensitized prostate cancer to capsaicin treatment. Finally, our experimental results indicated that capsaicin negatively modulates the activity of AR at the mRNA and protein levels by restoring miR-449a profiling in prostate cancer. In addition, increased expression of miR-449a may facilitate the sensitivity of prostate cancer to capsaicin treatment. Thus, capsaicin may be developed as a novel anti-AR drug for the therapy of prostate cancer.

  5. Intratumoral de novo steroid synthesis activates androgen receptor in castration-resistant prostate cancer and is upregulated by treatment with CYP17A1 inhibitors.

    Science.gov (United States)

    Cai, Changmeng; Chen, Sen; Ng, Patrick; Bubley, Glenn J; Nelson, Peter S; Mostaghel, Elahe A; Marck, Brett; Matsumoto, Alvin M; Simon, Nicholas I; Wang, Hongyun; Chen, Shaoyong; Balk, Steven P

    2011-10-15

    Relapse of castration-resistant prostate cancer (CRPC) that occurs after androgen deprivation therapy of primary prostate cancer can be mediated by reactivation of the androgen receptor (AR). One important mechanism mediating this AR reactivation is intratumoral conversion of the weak adrenal androgens DHEA and androstenedione into the AR ligands testosterone and dihydrotestosterone. DHEA and androstenedione are synthesized by the adrenals through the sequential actions of the cytochrome P450 enzymes CYP11A1 and CYP17A1, so that CYP17A1 inhibitors such as abiraterone are effective therapies for CRPC. However, the significance of intratumoral CYP17A1 and de novo androgen synthesis from cholesterol in CRPC, and the mechanisms contributing to CYP17A1 inhibitor resistance/relapse, remain to be determined. We report that AR activity in castration-resistant VCaP tumor xenografts can be restored through CYP17A1-dependent de novo androgen synthesis, and that abiraterone treatment of these xenografts imposes selective pressure for increased intratumoral expression of CYP17A1, thereby generating a mechanism for development of resistance to CYP17A1 inhibitors. Supporting the clinical relevance of this mechanism, we found that intratumoral expression of CYP17A1 was markedly increased in tumor biopsies from CRPC patients after CYP17A1 inhibitor therapy. We further show that CRPC cells expressing a progesterone responsive T877A mutant AR are not CYP17A1 dependent, but that AR activity in these cells is still steroid dependent and mediated by upstream CYP11A1-dependent intraturmoral pregnenolone/progesterone synthesis. Together, our results indicate that CRPCs resistant to CYP17A1 inhibition may remain steroid dependent and therefore responsive to therapies that can further suppress de novo intratumoral steroid synthesis.

  6. Androgen Metabolism Gene Polymorphisms, Associations with Prostate Cancer Risk and Pathological Characteristics: A Comparative Analysis between South African and Senegalese Men

    Directory of Open Access Journals (Sweden)

    Pedro Fernandez

    2012-01-01

    Full Text Available Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls, Mixed Ancestry (207 cases; 167 controls, and Black (25 cases; 20 controls men, as well as in Senegalese men (86 cases; 300 controls. Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men.

  7. Prostate cancer: assessing the effects of androgen-deprivation therapy using quantitative diffusion-weighted and dynamic contrast-enhanced MRI

    Energy Technology Data Exchange (ETDEWEB)

    Hoetker, Andreas M. [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States); Universitaetsmedizin Mainz, Department of Diagnostic and Interventional Radiology, Mainz (Germany); Mazaheri, Yousef [Memorial Sloan-Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Zheng, Junting; Moskowitz, Chaya S. [Memorial Sloan-Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Berkowitz, Joshua; Pei, Xin; Zelefsky, Michael J. [Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, New York, NY (United States); Lantos, Joshua E.; Hricak, Hedvig; Akin, Oguz [Memorial Sloan-Kettering Cancer Center, Department of Radiology, New York, NY (United States)

    2015-09-15

    To investigate the effects of androgen-deprivation therapy (ADT) on MRI parameters and evaluate their associations with treatment response measures. The study included 30 men with histopathologically confirmed prostate cancer who underwent MRI before and after initiation of ADT. Thirty-four tumours were volumetrically assessed on DW-MRI (n = 32) and DCE-MRI (n = 18), along with regions of interest in benign prostatic tissue, to calculate apparent diffusion coefficient (ADC) and transfer constant (K{sup trans}) values. Changes in MRI parameters and correlations with clinical parameters (change in prostate-specific antigen [PSA], treatment duration, PSA nadir) were assessed. Prostate volume and PSA values decreased significantly with therapy (p < 0.001). ADC values increased significantly in tumours and decreased in benign prostatic tissue (p < 0.05). Relative changes in ADC and absolute post-therapeutic ADC values differed significantly between tumour and benign tissue (p < 0.001). K{sup trans} decreased significantly only in tumours (p < 0.001); relative K{sup trans} changes and post-therapeutic values were not significantly different between tumour and benign tissue. The relative change in tumour ADC correlated significantly with PSA decrease. No changes were associated with treatment duration or PSA nadir. Multi-parametric MRI shows significant measurable changes in tumour and benign prostate caused by ADT and may help in monitoring treatment response. (orig.)

  8. Neuroendocrine differentiation in prostate cancer%前列腺癌的神经内分泌分化

    Institute of Scientific and Technical Information of China (English)

    Jingwen Wang; Yang Yao

    2008-01-01

    Hormonal therapy is an important treatment for advanced/metastatic prostate cancer. But it can induce neuroen-docrine (NE) differentiation in prostate cancer cells. These NE cells will secrete manifold neural peptide or hormones which can lead to androgen-independent growth of non-NE tumor cells. When this happens, hormonal therapy becomes useless and indicates bad prognosis. In this paper, the mechanism of neuroendocrine differentiation and its relationship with androgen-independent were reviewed.

  9. Reptides and Proteins Interacting with the Androgen Receptor

    NARCIS (Netherlands)

    D.J. van de Wijngaart (Dennis)

    2009-01-01

    textabstractAndrogens are important sex steroid hormones. The androgens testosterone and dihydrotestosterone (DHT) are essential for normal male sexual differentiation and for the development and maintenance of male reproductive tissues, including the prostate. Androgens mediate their effects by bin

  10. Fasting Blood Glucose and Lipid Profile Alterations following Twelve-Month Androgen Deprivation Therapy in Men with Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Hasan S. Sağlam

    2012-01-01

    Full Text Available Purpose. In this retrospective study, we aimed to investigate the effects of androgen deprivation therapy (ADT on blood glucose and blood cholesterol levels over a 12-month period. Materials and Methods. Between January 2010 and June 2012, the data of 44 patients with prostate cancer who were receiving ADT were collected from a hospital database. Patients with additional malignancy or diabetes and those who had been prescribed and were currently taking cholesterol-lowering medication were excluded from the study. Data (including fasting blood glucose levels and a cholesterol profile were collected and analysed statistically. A value <0.05 was considered statistically significant. Results. Twelve months after the initiation of ADT, fasting blood glucose (FBG, total cholesterol (TC, low-density lipoprotein (LDL cholesterol, high-density lipoprotein (HDL cholesterol, and triglyceride (TG levels changed. FBG, TC, LDL cholesterol, and TG increased significantly (, 0.000, 0.000, and 0.000, resp., while HDL cholesterol decreased (. Conclusion. ADT may increase FBG, TC, LDL cholesterol, and TG but decrease HDL cholesterol by the end of a year of treatment. Therefore, close followup may be needed as a consequence of one-year ADT regarding metabolic alterations.

  11. Strategies for Imaging Androgen Receptor Signaling Pathway in Prostate Cancer: Implications for Hormonal Manipulation and Radiation Treatment

    Directory of Open Access Journals (Sweden)

    Gravina Giovanni Luca

    2013-01-01

    Full Text Available Prostate cancer (Pca is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.

  12. Expanded risk groups help determine which prostate radiotherapy sub-group may benefit from adjuvant androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Williams Scott G

    2008-04-01

    Full Text Available Abstract Purpose To assess whether an expanded (five level risk stratification system can be used to identify the sub-group of intermediate risk patients with prostate cancer who benefit from combining androgen deprivation therapy (ADT with external beam radiotherapy (EBRT. Materials and methods Using a previously validated 5-risk group schema, a prospective non-randomized data set of 1423 men treated at the British Columbia Cancer Agency was assessed for the primary end point of biochemical control (bNED with the RTOG-ASTRO "Phoenix" definition (lowest PSA to date + 2 ng/mL, both with and without adjuvant ADT. The median follow-up was 5 years. Results There was no bNED benefit for ADT in the low or low intermediate groups but there was a statistically significant bNED benefit in the high intermediate, high and extreme risk groups. The 5-year bNED rates with and without ADT were 70% and 73% respectively for the low intermediate group (p = non-significant and 72% and 58% respectively for the high intermediate group (p = 0.002. Conclusion There appears to be no advantage to ADT where the Gleason score is 6 or less and PSA is 15 or less. ADT is beneficial in patients treated to standard dose radiation with Gleason 6 disease and a PSA greater than 15 or where the Gleason score is 7 or higher.

  13. GLI1 confers profound phenotypic changes upon LNCaP prostate cancer cells that include the acquisition of a hormone independent state.

    Directory of Open Access Journals (Sweden)

    Sandeep K Nadendla

    Full Text Available The GLI (GLI1/GLI2 transcription factors have been implicated in the development and progression of prostate cancer although our understanding of how they actually contribute to the biology of these common tumours is limited. We observed that GLI reporter activity was higher in normal (PNT-2 and tumourigenic (DU145 and PC-3 androgen-independent cells compared to androgen-dependent LNCaP prostate cancer cells and, accordingly, GLI mRNA levels were also elevated. Ectopic expression of GLI1 or the constitutively active ΔNGLI2 mutant induced a distinct cobblestone-like morphology in LNCaP cells that, regarding the former, correlated with increased GLI2 as well as expression of the basal/stem-like markers CD44, β1-integrin, ΔNp63 and BMI1, and decreased expression of the luminal marker AR (androgen receptor. LNCaP-GLI1 cells were viable in the presence of the AR inhibitor bicalutamide and gene expression profiling revealed that the transcriptome of LNCaP-GLI1 cells was significantly closer to DU145 and PC-3 cells than to control LNCaP-pBP (empty vector cells, as well as identifying LCN2/NGAL as a highly induced transcript which is associated with hormone independence in breast and prostate cancer. Functionally, LNCaP-GLI1 cells displayed greater clonal growth and were more invasive than control cells but they did not form colonies in soft agar or prostaspheres in suspension suggesting that they do not possess inherent stem cell properties. Moreover, targeted suppression of GLI1 or GLI2 with siRNA did not reverse the transformed phenotype of LNCaP-GLI1 cells nor did double GLI1/GLI2 knockdowns activate AR expression in DU145 or PC-3 cells. As such, early targeting of the GLI oncoproteins may hinder progression to a hormone independent state but a more detailed understanding of the mechanisms that maintain this phenotype is required to determine if their inhibition will enhance the efficacy of anti-hormonal therapy through the induction of a luminal

  14. Soy Phytochemicals and Tea Bioactive Components Synergistically Inhibit Androgen-Sensitive Human Prostate Tumors in Mice

    OpenAIRE

    Zhou, Jin-Rong; Yu, Lunyin; Zhong, Ying; Blackburn, George L.

    2003-01-01

    Although high doses of single bioactive agents may have potent anticancer effects, the chemopreventive properties of the Asian diet may result from interactions among several components that potentiate the activities of any single constituent. In Asia, where intake of soy products and tea consumption are very high, aggressive prostate cancer is significantly less prevalent in Asian men. The objective of the present study was to identify possible synergistic effects between soy and tea compone...

  15. A comparison of androgen deprivation therapy versus surgical castration for patients with advanced prostatic carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yu-hsiang LIN; Chien-lun CHEN; Chen-pang HOU; Phei-lang CHANG; Ke-hung TSUI

    2011-01-01

    Airn:To examine the outcomes of patients with advanced prostate carcinoma who underwent medical or surgical castration.Methods:A hundred twenty one consecutive cases of patients with advanced prostate carcinoma who underwent medicaI or surgical castration between 2001 and 2006 were retrospectively reviewed.Associations between clinicaI outcomes and prognostic scoring factors were determined based on the Reijke study.In the surgical and medical castration groups.the impact on the prostate-specific antigen(PSA)normalization rate,the rebound rate and the disease-free survivaI rate were evaluated.The mean foIlow-up was 36.1months.Results:In the initial 12 months.there were no statisticaI differences in the PSA normalization rate and the PSA rebound rate between the two groups.However,the PSA rebound rate after the 12th month(20.90%vs 40.74%.P=-0.0175)and the 18th month PSA normalization rate(59.70%vs 37.04%.P=0.0217)differed significantly between the two groups,and these differences were maintained to the end of the study.When comparing patients grouped according to Reijke prognosis scores.there was no difference between medical and surgical castration for the good prognosis group.However, among the patients given a poor prognosis,surgical castration was superior in terms of the PSA normalization rate,the PSA rebound rate.the tumor progression-free survival rate(P<0.001)and the overalI survivaI rate (P<0.001).Conclusion:Advanced prostate carcinoma patients with poor pretreatment prognosis scores should undergo surgical castration rather than medical castration for better PSA rebound rates and overaII survival.

  16. Is Androgen Deprivation Therapy Necessary in All Intermediate-Risk Prostate Cancer Patients Treated in the Dose Escalation Era?

    Energy Technology Data Exchange (ETDEWEB)

    Castle, Katherine O., E-mail: kocastle@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Hoffman, Karen E.; Levy, Lawrence B.; Lee, Andrew K.; Choi, Seungtaek; Nguyen, Quynh N.; Frank, Steven J.; Pugh, Thomas J.; McGuire, Sean E.; Kuban, Deborah A. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

    2013-03-01

    Purpose: The benefit of adding androgen deprivation therapy (ADT) to dose-escalated radiation therapy (RT) for men with intermediate-risk prostate cancer is unclear; therefore, we assessed the impact of adding ADT to dose-escalated RT on freedom from failure (FFF). Methods: Three groups of men treated with intensity modulated RT or 3-dimensional conformal RT (75.6-78 Gy) from 1993-2008 for prostate cancer were categorized as (1) 326 intermediate-risk patients treated with RT alone, (2) 218 intermediate-risk patients treated with RT and ≤6 months of ADT, and (3) 274 low-risk patients treated with definitive RT. Median follow-up was 58 months. Recursive partitioning analysis based on FFF using Gleason score (GS), T stage, and pretreatment PSA concentration was applied to the intermediate-risk patients treated with RT alone. The Kaplan-Meier method was used to estimate 5-year FFF. Results: Based on recursive partitioning analysis, intermediate-risk patients treated with RT alone were divided into 3 prognostic groups: (1) 188 favorable patients: GS 6, ≤T2b or GS 3+4, ≤T1c; (2) 71 marginal patients: GS 3+4, T2a-b; and (3) 68 unfavorable patients: GS 4+3 or T2c disease. Hazard ratios (HR) for recurrence in each group were 1.0, 2.1, and 4.6, respectively. When intermediate-risk patients treated with RT alone were compared to intermediate-risk patients treated with RT and ADT, the greatest benefit from ADT was seen for the unfavorable intermediate-risk patients (FFF, 74% vs 94%, respectively; P=.005). Favorable intermediate-risk patients had no significant benefit from the addition of ADT to RT (FFF, 94% vs 95%, respectively; P=.85), and FFF for favorable intermediate-risk patients treated with RT alone approached that of low-risk patients treated with RT alone (98%). Conclusions: Patients with favorable intermediate-risk prostate cancer did not benefit from the addition of ADT to dose-escalated RT, and their FFF was nearly as good as patients with low-risk disease

  17. Influences of androgen on the growth of human prostate cancer PC-3M model in nude mice and the changes of the androgen receptor levels and protein kinase C activity

    International Nuclear Information System (INIS)

    Nude mice bearing transplanted human prostate cancer cell line PC-3M were treated with male sex hormone. Results demonstrated that low dose of testosterone propionate (TP) (50 mg/kg wt.) stimulated the tumor growth, and the androgen receptor (AR) levels and protein kinase C (PKC) activity were elevated in the tumor tissue. On the contrary higher dose of TP (400 mg/kg wt.) inhibited the tumor growth, and the AR level and PKC activity in tumor tissue were reduced significantly. These results showed that TP has a biphasic effect on the growth of human prostate cancer PC-3M cell line. The mechanism of the biphasic effect and its relationship between AR and PKC levels are also discussed

  18. Pharmacoeconomics of Available Treatment Options for Metastatic Prostate Cancer

    OpenAIRE

    Zeliadt, Steven B.; Penson, David F.

    2007-01-01

    The resources devoted to managing metastatic prostate cancer are enormous, yet little attention has been given to directly measuring the economic consequences of treatment alternatives. The purpose of this article was to evaluate the pharmacoeconomics of available treatments for metastatic prostate cancer, including hormone-sensitive disease, androgen-independent prostate cancer and locally advanced/progressive disease. We identified 58 articles addressing economic issues related to metastati...

  19. Cyclin-dependent kinase 5 acts as a critical determinant of AKT-dependent proliferation and regulates differential gene expression by the androgen receptor in prostate cancer cells.

    Science.gov (United States)

    Lindqvist, Julia; Imanishi, Susumu Y; Torvaldson, Elin; Malinen, Marjo; Remes, Mika; Örn, Fanny; Palvimo, Jorma J; Eriksson, John E

    2015-06-01

    Contrary to cell cycle-associated cyclin-dependent kinases, CDK5 is best known for its regulation of signaling processes in differentiated cells and its destructive activation in Alzheimer's disease. Recently, CDK5 has been implicated in a number of different cancers, but how it is able to stimulate cancer-related signaling pathways remains enigmatic. Our goal was to study the cancer-promoting mechanisms of CDK5 in prostate cancer. We observed that CDK5 is necessary for proliferation of several prostate cancer cell lines. Correspondingly, there was considerable growth promotion when CDK5 was overexpressed. When examining the reasons for the altered proliferation effects, we observed that CDK5 phosphorylates S308 on the androgen receptor (AR), resulting in its stabilization and differential expression of AR target genes including several growth-priming transcription factors. However, the amplified cell growth was found to be separated from AR signaling, further corroborated by CDK5-dependent proliferation of AR null cells. Instead, we found that the key growth-promoting effect was due to specific CDK5-mediated AKT activation. Down-regulation of CDK5 repressed AKT phosphorylation by altering its intracellular localization, immediately followed by prominent cell cycle inhibition. Taken together, these results suggest that CDK5 acts as a crucial signaling hub in prostate cancer cells by controlling androgen responses through AR, maintaining and accelerating cell proliferation through AKT activation, and releasing cell cycle breaks. PMID:25851605

  20. Football training improves lean body mass in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

    Uth, J; Hornstrup, Therese; Schmidt, Jakob Friis;

    2014-01-01

    ). Fifty-seven men aged 67 (range: 43-74) were randomly assigned to a football group (FG, n = 29) or a usual care control group (CON, n = 28). The primary outcome was change in lean body mass (LBM) assessed by dual-energy X-ray absorptiometry scanning. Secondary outcomes included changes in knee.......7%; 95%CI 1.3-0.0; P = 0.06), but these changes were not significantly different from CON. In conclusion, football training over 12 weeks improved LBM and muscle strength compared with usual care in men with prostate cancer receiving ADT....

  1. Prognostic Value of Abnormal p53 Expression in Locally Advanced Prostate Cancer Treated With Androgen Deprivation and Radiotherapy: A Study Based on RTOG 9202

    International Nuclear Information System (INIS)

    Purpose: The goal of this study was to verify the significance of p53 as a prognostic factor in Radiation Therapy Oncology Group 9202, which compared short-term androgen deprivation (STAD) with radiation therapy (RT) to long-term androgen deprivation + RT in men with locally advanced prostate cancer (Pca). Methods and Materials: Tumor tissue was sufficient for p53 analysis in 777 cases. p53 status was determined by immunohistochemistry. Abnormal p53 expression was defined as 20% or more tumor cells with positive nuclei. Univariate and multivariate Cox proportional hazards models were used to evaluate the relationships of p53 status to patient outcomes. Results: Abnormal p53 was detected in 168 of 777 (21.6%) cases, and was significantly associated with cause-specific mortality (adjusted hazard ratio [HR] = 1.89; 95% confidence interval (CI) 1.14 - 3.14; p = 0.014) and distant metastasis (adjusted HR = 1.72; 95% CI 1.13-2.62; p = 0.013). When patients were divided into subgroups according to assigned treatment, only the subgroup of patients who underwent STAD + RT showed significant correlation between p53 status and cause-specific mortality (adjusted HR = 2.43; 95% CI = 1.32-4.49; p = 0.0044). When patients were divided into subgroups according to p53 status, only the subgroup of patients with abnormal p53 showed significant association between assigned treatment and cause-specific mortality (adjusted HR = 3.81; 95% CI 1.40-10.37; p = 0.0087). Conclusions: Abnormal p53 is a significant prognostic factor for patients with prostate cancer who undergo short-term androgen deprivation and radiotherapy. Long-term androgen deprivation may significantly improve the cause-specific survival for those with abnormal p53

  2. Muscle function, physical performance and body composition changes in men with prostate cancer undergoing androgen deprivation therapy

    Institute of Scientific and Technical Information of China (English)

    Thomas W Storer; Renee Miciek; Thomas G Travison

    2012-01-01

    Prostate cancer (PCa) is the most common visceral malignancy in men with androgen deprivation therapy (ADT) the preferred therapy to suppress testosterone production and hence tumor growth.Despite its effectiveness in lowering testosterone,ADT is associated with side effects including loss of muscle mass,diminished muscle strength,decrements in physical performance,earlier fatigue and declining quality of life.This review reports a survey of the literature with a focus on changes in muscle strength,physical function and body composition,due to short-term and long-term ADT.Studies in these areas are sparse,especially well-controlled,prospective randomized trials.Cross-sectional and longitudinal data (up to 2 years) for men with PCa treated with ADT as well as patients with PCa not receiving ADT and age-matched healthy men are presented when available.Based on limited longitudinal data,the adverse effects of ADT on muscle function,physical performance and body composition occur shortly after the onset of ADT andtend to persist and worsen over time.Exercise training is a safe and effective intervention for mitigating these changes and initial guidelines for exercise program design for men with PCa have been published by the American College of Sports Medicine.Disparities in study duration,typos of studies and other patient-specific variables such as time since diagnosis,cancer stage and comorbidities may all affect an understanding of the influence of ADT on health,physical performance and mortality.

  3. A quality assurance audit: phase iii trial of maximal androgen deprivation in prostate cancer (TROG 96.01)

    International Nuclear Information System (INIS)

    In 1997 the Trans-Tasman Radiation Oncology Group (TROG) performed a quality assurance (QA) audit of its phase III randomized clinical trial investigating the effectiveness of different durations of maximal androgen deprivation prior to and during definitive radiation therapy for locally advanced carcinoma of the prostate (TROG 96.01). The audit reviewed a total of 60 cases from 15 centres across Australia and New Zealand. In addition to verification of technical adherence to the protocol, the audit also incorporated a survey of centre planning techniques and a QA time/cost analysis. The present report builds on TROG's first technical audit conducted in 1996 for the phase III accelerated head and neck trial (TROG 91.01) and highlights the significant progress TROG has made in the interim period. The audit provides a strong validation of the results of the 96.01 trial, as well as valuable budgeting and treatment planning information for future trials. Overall improvements were detected in data quality and quantity, and in protocol compliance, with a reduction in the rate of unacceptable protocol violations from 10 to 4%. Audit design, staff education and increased data management resources were identified as the main contributing factors to these improvements. In addition, a budget estimate of $100 per patient has been proposed for conducting similar technical audits. The next major QA project to be undertaken by TROG during the period 1998-1999 is an intercentre dosimetry study. Trial funding and staff education have been targeted as the key major issues essential to the continued success and expansion of TROG's QA programme. Copyright (1999) Blackwell Science Pty Ltd

  4. Prostate cancer stem cells

    OpenAIRE

    Tu, Shi-Ming; Lin, Sue-Hwa

    2011-01-01

    Stem cells have long been implicated in prostate glandular formation. The prostate undergoes regression after androgen deprivation and regeneration after testosterone replacement. Regenerative studies suggest that these cells are found in the proximal ducts and basal layer of the prostate. Many characteristics of prostate cancer indicate that it originates from stem cells. For example, the putative AR− status of prostate stem cells renders them inherently insensitive to androgen blockade ther...

  5. Regulation of the pentose phosphate pathway by an androgen receptor-mTOR-mediated mechanism and its role in prostate cancer cell growth.

    Science.gov (United States)

    Tsouko, E; Khan, A S; White, M A; Han, J J; Shi, Y; Merchant, F A; Sharpe, M A; Xin, L; Frigo, D E

    2014-05-26

    Cancer cells display an increased demand for glucose. Therefore, identifying the specific aspects of glucose metabolism that are involved in the pathogenesis of cancer may uncover novel therapeutic nodes. Recently, there has been a renewed interest in the role of the pentose phosphate pathway in cancer. This metabolic pathway is advantageous for rapidly growing c