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Sample records for androgen independent prostate

  1. 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...

  2. 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

  3. 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....

  4. 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...

  5. A comparative study of glycoproteomes in androgen-sensitive and -independent prostate cancer cell lines

    OpenAIRE

    Drabik, Anna; Ciołczyk-Wierzbicka, Dorota; Dulińska-Litewka, Joanna; Bodzoń-Kułakowska, Anna; Suder, Piotr; Silberring, Jerzy; Laidler, Piotr

    2013-01-01

    Prostate cancer is one of the most common malignancies in men and is predicted to be the second leading cause of cancer-related deaths. After 6–18 months, hormone ablation treatment results in androgen-independent growth of cancer cells, metastasis and progression. The mechanism of androgen-independent growth of prostatic carcinoma cells is still unknown. Identification of factors that facilitate the transition from androgen-dependent to independent states is crucial in designing future diagn...

  6. 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....

  7. 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

  8. 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.

  9. 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...

  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.

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    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. 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.

  16. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  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. 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. PMID:26841317

  20. 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.

  1. 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...

  2. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    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

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

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    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.

  5. 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...

  6. 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

  7. 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.

  8. Co-Targeting Prostate Cancer Epithelium and Bone Stroma by Human Osteonectin-Promoter–Mediated Suicide Gene Therapy Effectively Inhibits Androgen-Independent Prostate Cancer Growth

    Science.gov (United States)

    Sung, Shian-Ying; Chang, Junn-Liang; Chen, Kuan-Chou; Yeh, Shauh-Der; Liu, Yun-Ru; Su, Yen-Hao; Hsueh, Chia-Yen; Chung, Leland W. K.; Hsieh, Chia-Ling

    2016-01-01

    Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor–promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter–driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers. PMID:27054343

  9. 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...

  10. 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...

  11. 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

  12. 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)

  13. Inverse baseline expression pattern of the NEP/neuropeptides and NFκB/proteasome pathways in androgen-dependent and androgen-independent prostate cancer cells

    Directory of Open Access Journals (Sweden)

    Apostolou Effie

    2011-05-01

    Full Text Available Abstract Background Castration-resistance in prostate cancer (PC is a critical event hallmarking a switch to a more aggressive phenotype. Neuroendocrine differentiation and upregulation of NFκB transcriptional activity are two mechanisms that have been independently linked to this process. Methods We investigated these two pathways together using in vitro models of androgen-dependent (AD and androgen-independent (AI PC. We measured cellular levels, activity and surface expression of Neutral Endopeptidase (NEP, levels of secreted Endothelin-1 (ET-1, levels, sub-cellular localisation and DNA binding ability of NFκB, and proteasomal activity in human native PC cell lines (LnCaP and PC-3 modelling AD and AI states. Results At baseline, AD cells were found to have high NEP expression and activity and low secreted ET-1. In contrast, they exhibited a low-level activation of the NFκB pathway associated with comparatively low 20S proteasome activity. The AI cells showed the exact mirror image, namely increased proteasomal activity resulting in a canonical pathway-mediated NFκB activation, and minimal NEP activity with increased levels of secreted ET-1. Conclusions Our results seem to support evidence for divergent patterns of expression of the NFκB/proteasome pathway with relation to components of the NEP/neuropeptide axis in PC cells of different level of androgen dependence. NEP and ET-1 are inversely and directly related to an activated state of the NFκB/proteasome pathway, respectively. A combination therapy targeting both pathways may ultimately prove to be of benefit in clinical practice.

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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

    International Nuclear Information System (INIS)

    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.

  2. 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...

  3. 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 ...

  4. Androgen receptor profiling predicts prostate cancer outcome

    OpenAIRE

    Stelloo, Suzan; Nevedomskaya, Ekaterina; van der Poel, Henk G.; de Jong, Jeroen; van Leenders, Geert JLH; Jenster, Guido; Wessels, Lodewyk FA; Bergman, Andries M; Zwart, Wilbert

    2015-01-01

    Prostate cancer is the second most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively. To identify prognostic markers and to determine causal players in prostate cancer progression, we assessed changes in chromatin state during tumor development and progression. Based on this, we assessed genomewide androgen receptor/chromatin binding and identified a distinct androgen receptor/chromati...

  5. 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...

  6. 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.

  7. 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...

  8. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela;

    2011-01-01

    epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT...

  9. 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-...

  10. 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...

  11. 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

  12. 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.

  13. Reducible self-assembling cationic polypeptide-based micelles mediate co-delivery of doxorubicin and microRNA-34a for androgen-independent prostate cancer therapy.

    Science.gov (United States)

    Yao, Chong; Liu, Jiyong; Wu, Xin; Tai, Zongguang; Gao, Yuan; Zhu, Quangang; Li, Jiafei; Zhang, Lijuan; Hu, Chuling; Gu, Fenfen; Gao, Jing; Gao, Shen

    2016-06-28

    The co-delivery of chemotherapeutic drugs and microRNAs (miR) represents a promising strategy for tumor therapy due to the synergistic effect achieved. In the present study, hydrophobic doxorubicin (DOX) and negatively charged miR-34a were simultaneously delivered via a reducible self-assembling disulfide cross-linked stearyl-peptide-based micellar system (SHRss) using poly(l-arginine)-poly(l-histidine)-stearoyl as the copolymer building unit. The nanoscale SHRss micelles exhibited a low critical micelle concentration (CMC) with positive surface charge. In addition, the present micellar system facilitated the escape of miR-34a from the endosome and release of DOX into the cell nucleus, leading to the downregulation of silent information regulator 1 (SIRT1) expression and inhibition of DU145 and PC3 androgen-independent prostate cancer cell proliferation. In addition, DOX and miR-34a, delivered by SHRss micelles, passively targeted tumor tissue. Furthermore, a synergistic anti-proliferative effect was observed compared with DOX or miR-34a treatment alone in vivo. Our results demonstrate that the SHRss micelles developed in the present study represent a promising approach for combined delivery of gene agents and hydrophobic chemotherapeutic drugs in cancer therapy. PMID:27126903

  14. 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

  15. 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

  16. 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

  17. 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.

  18. Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

    OpenAIRE

    Li, Zhi Gang; Mathew, Paul; Yang, Jun; Starbuck, Michael W.; Zurita, Amado J.; Liu, Jie; Sikes, Charles; Multani, Asha S.; Efstathiou, Eleni; Lopez, Adriana; Wang, Jing; Fanning, Tina V.; Prieto, Victor G.; Kundra, Vikas; Vazquez, Elba S

    2008-01-01

    In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor–negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as...

  19. 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...

  20. 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...

  1. 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

  2. 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...

  3. Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells

    DEFF Research Database (Denmark)

    Dahl, Malin; Bouchelouche, Pierre; Kramer-Marek, Gabriela; Capala, Jacek; Nordling, Jørgen; Bouchelouche, Kirsten

    2011-01-01

    epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT......Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate......-qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 μM sarcosine for 24 h resulted in a 58% increase of the HER2/neu m...

  4. 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

  5. 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.

  6. 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.

  7. Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer

    Science.gov (United States)

    Antonarakis, Emmanuel S.

    2016-01-01

    While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling. Nevertheless, additional androgen-pathway resistance usually develops to these novel hormonal therapies. In this review, we will discuss the resistance mechanisms to modern androgen-axis modulators and how these alterations can influence a patient's response to novel hormonal therapy. We conceptualize these resistance pathways as three broad categories: (1) reactivation of androgen/AR-signaling, (2) AR bypass pathways, and (3) androgen/AR-independent mechanisms. We highlight examples of each, as well as potential therapeutic approaches to overcome these resistance mechanisms. PMID:26902623

  8. 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...

  9. Outsmarting androgen receptor: creative approaches for targeting aberrant androgen signaling in advanced prostate cancer

    OpenAIRE

    Karen E Knudsen; Kelly, William Kevin

    2011-01-01

    Prostatic adenocarcinomas are reliant on androgen receptor (AR) activity for survival and progression. Therefore, first-line therapeutic intervention for disseminated disease entails the use of AR-directed therapeutics, achieved through androgen deprivation and direct AR antagonists. While initially effective, recurrent, ‘castrate-resistant’ prostate cancers arise, for which there is no durable means of treatment. An abundance of clinical study and preclinical modeling has led to the revelati...

  10. 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...

  11. 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.

  12. 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

  13. 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.

  14. Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

    International Nuclear Information System (INIS)

    Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor. The human CRPC xenograft LuCaP 35V was implanted into orchiectomized male SCID mice and established tumors were treated with placebo, 17β-estradiol or 17β-estradiol and estrogen receptor antagonist ICI 182,780. Effects of 17β-estradiol on tumor growth were evaluated and tissue testosterone (T) and dihydrotestosterone (DHT) evaluated by mass spectrometry. Treatment of LuCaP 35V with 17β-estradiol slowed tumor growth compared to controls (tumor volume at day 21: 785 ± 81 mm3 vs. 1195 ± 84 mm3, p = 0.002). Survival was also significantly improved in animals treated with 17β-estradiol (p = 0.03). The addition of the estrogen receptor antagonist ICI 182,780 did not significantly change survival or growth. 17β-estradiol in the presence and absence of ICI 182,780 suppressed tumor testosterone (T) and dihydrotestosterone (DHT) as assayed by mass spectrometry. Tissue androgens in placebo treated LuCaP 35V xenografts were; T = 0.71 ± 0.28 pg/mg and DHT = 1.73 ± 0.36 pg/mg. In 17β-estradiol treated LuCaP35V xenografts the tissue androgens were, T = 0.20 ± 0.10 pg/mg and DHT = 0.15 ± 0.15 pg/mg, (p < 0.001 vs. controls). Levels of T and DHT in control liver tissue were < 0.2 pg/mg. CRPC in anorchid animals maintains tumoral androgen levels despite castration. 17β-estradiol significantly suppressed tumor T and DHT and inhibits growth of CRPC in an estrogen receptor independent manner. The ability to manipulate tumoral androgens will be critical in the development and testing of agents targeting CRPC through tissue steroidogenesis

  15. 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...

  16. 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

  17. MDM2 Inhibition Sensitizes Prostate Cancer Cells to Androgen Ablation and Radiotherapy in a p53-Dependent Manner

    OpenAIRE

    Felix Y. Feng; Yu Zhang; Vishal Kothari; Joseph R. Evans; Jackson, William C; Wei Chen; Johnson, Skyler B.; Connor Luczak; Shaomeng Wang; Hamstra, Daniel A

    2016-01-01

    PURPOSE: Increased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer. EXPERIMENTAL DESIGN: The effect of M...

  18. 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 ...

  19. 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...

  20. 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...

  1. 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.

  2. 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...

  3. Assessing hypoxia in androgen dependent prostate tumour models using EF5

    International Nuclear Information System (INIS)

    Hormone withdrawal therapy is an important treatment modality in prostate cancer in addition to surgery or radiotherapy. Most tumours respond to androgen ablation and regress; but eventually the tumours become androgen independent and can re-grow more aggressively. Rationale: The timing of radiation would be important if tumour hypoxia varies during hormone therapy. We are investigating the effect of androgen status on tumour hypoxia in murine prostate models. Tools: Initially, the Shionogi murine system, a hormone dependent tumour model for prostate cancer, was used with the nitroimidazole, EF5, to study changes in hypoxia during tumour progression. Methods: EF5 was injected into mice 3 hours before tumour harvest; half the tumour was disaggregated and analysed with flow cytometry while the other half was frozen for sectioning. The Cy3/5-tagged monoclonal antibody ELK3-51 was then used to assess EF5 binding in cells or in tissue sections (EF5 binding occurs in the absence of oxygen). Results: Tissue sections from androgen dependent (AD) tumours had variable regions of EF5 binding before castration; little EF5 binding was seen in tumours from castrated (CX) mice. However, androgen independent (AI) tumours (21 days post-castration) showed high levels of well-distributed EF5 binding. Flow cytometry indicated that the percentage of cells from AD, CX and AI tumours with levels of EF5 binding greater than control tumours (not exposed to EF5) were ∼30%, ∼2% and ∼50%, respectively. The extent of hypoxia did not appear to be related to tumour size. Our results at other time points, and in the human LNCaP model will be presented. Implications: If hypoxia is also variable in human prostate tumours, then it would be important to choose appropriate timing for radiotherapy or determine hypoxia on an individual basis in prostate patients

  4. 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...

  5. 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 ...

  6. 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

  7. Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

    Science.gov (United States)

    Li, Zhi Gang; Mathew, Paul; Yang, Jun; Starbuck, Michael W.; Zurita, Amado J.; Liu, Jie; Sikes, Charles; Multani, Asha S.; Efstathiou, Eleni; Lopez, Adriana; Wang, Jing; Fanning, Tina V.; Prieto, Victor G.; Kundra, Vikas; Vazquez, Elba S.; Troncoso, Patricia; Raymond, Austin K.; Logothetis, Christopher J.; Lin, Sue-Hwa; Maity, Sankar; Navone, Nora M.

    2008-01-01

    In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor–negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer–induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor–null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells. PMID:18618013

  8. Androgen receptor-negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms.

    Science.gov (United States)

    Li, Zhi Gang; Mathew, Paul; Yang, Jun; Starbuck, Michael W; Zurita, Amado J; Liu, Jie; Sikes, Charles; Multani, Asha S; Efstathiou, Eleni; Lopez, Adriana; Wang, Jing; Fanning, Tina V; Prieto, Victor G; Kundra, Vikas; Vazquez, Elba S; Troncoso, Patricia; Raymond, Austin K; Logothetis, Christopher J; Lin, Sue-Hwa; Maity, Sankar; Navone, Nora M

    2008-08-01

    In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells. PMID:18618013

  9. 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.

  10. 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.

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

    International Nuclear Information System (INIS)

    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. 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. 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. Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer

  12. 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...

  13. 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...

  14. 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

  15. 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...

  16. 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....

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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...

  2. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Kai-Xin; Firus, Jessica; Prieur, Brenda [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Jia, William [Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada); Rennie, Paul S., E-mail: prennie@interchange.ubc.ca [The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6 (Canada); Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6 (Canada)

    2011-03-24

    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.

  4. 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)

  5. 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.

  6. 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

  7. 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...

  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. 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...

  10. 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 ...

  11. 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.

  12. 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.

  13. 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

  14. Prostate cancer stem cells: the role of androgen and estrogen receptors.

    Science.gov (United States)

    Di Zazzo, Erika; Galasso, Giovanni; Giovannelli, Pia; Di Donato, Marzia; Di Santi, Annalisa; Cernera, Gustavo; Rossi, Valentina; Abbondanza, Ciro; Moncharmont, Bruno; Sinisi, Antonio Agostino; Castoria, Gabriella; Migliaccio, Antimo

    2016-01-01

    Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment.In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy. PMID:26506594

  15. Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate

    Energy Technology Data Exchange (ETDEWEB)

    Labrie, C.; Simard, J.; Zhao, H.F.; Belanger, A.; Pelletier, G.; Labrie, F. (Laval Univ. Medical Center, Quebec (Canada))

    1989-06-01

    Androgens play a major role in the development, growth, and function of accessory sexual organs, especially the prostate. However, the testis is not the sole source of circulating androgens in man, since the adrenal gland secretes dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (delta 4-dione) in large quantities. The aim of the present study was to investigate the effect of plasma concentrations of DHEA and delta 4-dione similar to those found in adult man on sensitive and specific markers of androgen action in the rat ventral prostate. In addition to ventral prostate weight, we have measured the steady state levels of the mRNAs encoding the C1 component of rat prostatic binding protein (PBP-C1) and spermine-binding protein (SBP) using 35S-labeled cDNA probes for in situ hybridization. One week after castration, ventral prostate weight fell 84%, while prostatic 5 alpha-dihydrotestosterone (DHT) and androgen-dependent mRNAs were undetectable. When administered via Silastic implants to castrated adult rats for 1 week, plasma concentrations of 1.37 +/- 0.06 ng/ml DHEA or 0.43 +/- 0.08 ng/ml delta 4-dione independently caused increases in ventral prostate weight to 33% and 65% of normal values, respectively. The same plasma levels of DHEA and delta 4-dione resulted in high intraprostatic levels of DHT to 1.19 +/- 0.34 and 3.66 +/- 0.89 ng/g tissue, respectively. Furthermore, DHEA caused an increase in the steady state levels of PBP-C1 and SBP mRNAs to 50% and 57% of the normal state, respectively, while delta 4-dione caused increases corresponding to 80% and 119% of control values, respectively. Castrated adult rats receiving testosterone at a concentration of 1.66 +/- 0.37 ng/ml plasma maintained normal ventral prostate weight and gene expression levels.

  16. Stimulation of androgen-dependent gene expression by the adrenal precursors dehydroepiandrosterone and androstenedione in the rat ventral prostate

    International Nuclear Information System (INIS)

    Androgens play a major role in the development, growth, and function of accessory sexual organs, especially the prostate. However, the testis is not the sole source of circulating androgens in man, since the adrenal gland secretes dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione (delta 4-dione) in large quantities. The aim of the present study was to investigate the effect of plasma concentrations of DHEA and delta 4-dione similar to those found in adult man on sensitive and specific markers of androgen action in the rat ventral prostate. In addition to ventral prostate weight, we have measured the steady state levels of the mRNAs encoding the C1 component of rat prostatic binding protein (PBP-C1) and spermine-binding protein (SBP) using 35S-labeled cDNA probes for in situ hybridization. One week after castration, ventral prostate weight fell 84%, while prostatic 5 alpha-dihydrotestosterone (DHT) and androgen-dependent mRNAs were undetectable. When administered via Silastic implants to castrated adult rats for 1 week, plasma concentrations of 1.37 +/- 0.06 ng/ml DHEA or 0.43 +/- 0.08 ng/ml delta 4-dione independently caused increases in ventral prostate weight to 33% and 65% of normal values, respectively. The same plasma levels of DHEA and delta 4-dione resulted in high intraprostatic levels of DHT to 1.19 +/- 0.34 and 3.66 +/- 0.89 ng/g tissue, respectively. Furthermore, DHEA caused an increase in the steady state levels of PBP-C1 and SBP mRNAs to 50% and 57% of the normal state, respectively, while delta 4-dione caused increases corresponding to 80% and 119% of control values, respectively. Castrated adult rats receiving testosterone at a concentration of 1.66 +/- 0.37 ng/ml plasma maintained normal ventral prostate weight and gene expression levels

  17. 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.

  18. 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)

  19. 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

  20. 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

  1. 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...... 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...

  2. 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

  3. 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

  4. 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

  5. Prostate cancer stem cells: the role of androgen and estrogen receptors

    OpenAIRE

    Di Zazzo, Erika; Galasso, Giovanni; Giovannelli, Pia; Di Donato, Marzia; Di Santi, Annalisa; Cernera, Gustavo; Rossi, Valentina; Abbondanza, Ciro; Moncharmont, Bruno; Sinisi, Antonio Agostino; Castoria, Gabriella; Migliaccio, Antimo

    2015-01-01

    Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable. Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells...

  6. 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)

  7. Vitamin K2, a Naturally Occurring Menaquinone, Exerts Therapeutic Effects on Both Hormone-Dependent and Hormone-Independent Prostate Cancer Cells

    OpenAIRE

    André Kajdacsy-Balla; Bosland, Maarten C.; Aoshuang Chen; Gouxing Zheng; Ramaswamy Kalyanasundaram; Gajalakshmi Dakshinamoorthy; Shetty, Aditya V.; Abhilash Samykutty; Munirathinam Gnanasekar

    2013-01-01

    In recent years, several studies have shown that vitamin k2 (VK2) has anticancer activity in a variety of cancer cells. The antitumor effects of VK2 in prostate cancer are currently not known. In the present study, we sought to characterize the anticancer potential of VK2 in both androgen-dependent and -independent prostate cancer cells. Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 depe...

  8. 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...

  9. Risk of Diabetes among Patients Receiving Primary Androgen Deprivation Therapy for Clinically Localized Prostate Cancer

    Science.gov (United States)

    Tsai, Huei-Ting; Keating, Nancy L.; Van Den Eeden, Stephen K.; Haque, Reina; Cassidy-Bushrow, Andrea E.; Yood, Marianne Ulcickas; Smith, Matthew R.; Potosky, Arnold L.

    2015-01-01

    Purpose Androgen deprivation therapy may increase diabetes risk. As the benefits of primary androgen deprivation therapy for localized prostate cancer are controversial, and most prostate cancer survivors are of advanced age with comorbidities, it is important to determine if primary androgen deprivation therapy increases the risk of diabetes and to determine the susceptibility factors. Materials and Methods We conducted a retrospective cohort study of 12,191 men diagnosed with incident localized prostate cancer during 1995 to 2008, age 35 to 100 years, and without diabetes or receipt of prostatectomy or radiation 1 year after diagnosis. Patients were enrolled in 1 of 3 managed health plans and followed through 2010. Primary androgen deprivation therapy was defined as androgen deprivation therapy within 1 year after diagnosis. Incident diabetes was ascertained using inpatient and outpatient diagnosis codes, diabetes medications and hemoglobin A1c values. We estimated primary androgen deprivation therapy associated diabetes risk using Cox proportional hazard models in conventional and propensity score analyses. Results Diabetes developed in 1,203 (9.9%) patients during followup (median 4.8 years) with incidence rates of 2.5 and 1.6 events per 100 person-years in the primary androgen deprivation therapy and nonprimary androgen deprivation therapy groups, respectively. Primary androgen deprivation therapy was associated with a 1.61-fold increased diabetes risk (95% CI 1.38–1.88). The number needed to harm was 29. The association was stronger in men age 70 or younger than in older men (HR 2.25 vs 1.40, p value for interaction = 0.008). Conclusions Primary androgen deprivation therapy may increase diabetes risk by 60% and should be used with caution when managing localized prostate cancer. Because of the consistent association between androgen deprivation therapy and greater diabetes risk across disease states, we recommend routine screening and lifestyle

  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. 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

  13. 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...

  14. GnRH agonists and the rapidly increasing use of combined androgen blockade in prostate cancer.

    Science.gov (United States)

    Labrie, Fernand

    2014-08-01

    The discovery of medical castration with GnRH agonists in 1979 rapidly replaced surgical castration and high doses of estrogens for the treatment of prostate cancer. Soon afterwards, it was discovered that androgens were made locally in the prostate from the inactive precursor DHEA of adrenal origin, a mechanism called intracrinology. Taking into account these novel facts, combined androgen blockade (CAB) using a pure antiandrogen combined with castration in order to block the two sources of androgens was first published in 1982. CAB was the first treatment shown in randomized and placebo-controlled trials to prolong life in prostate cancer, even at the metastatic stage. Most importantly, the results recently obtained with the novel pure antiandrogen enzalutamide as well as with abiraterone, an inhibitor of 17α-hydroxylase in castration-resistant prostate cancer, has revitalized the CAB concept. The effects of CAB observed on survival of heavily pretreated patients further demonstrates the importance of the androgens made locally in the prostate and are a strong motivation to apply CAB to efficiently block all sources of androgens earlier at start of treatment and, even better, before metastasis occurs. The future of research in this field thus seems to be centered on the development of more potent blockers of androgens formation and action in order to obtain better results at the metastatic stage and, for the localized stage, reduce the duration of treatment required to achieve complete apoptosis and control of prostate cancer proliferation before it reaches the metastatic or noncurable stage. PMID:24825748

  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. 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

  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. 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

  19. 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.

  20. 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.

  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. 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.

  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. 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

  6. 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.

  7. 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

    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...... (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....

  8. 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

  9. 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.

  10. Growth inhibition of human prostate cells in vitro by novel inhibitors of androgen synthesis.

    Science.gov (United States)

    Klus, G T; Nakamura, J; Li, J S; Ling, Y Z; Son, C; Kemppainen, J A; Wilson, E M; Brodie, A M

    1996-11-01

    The long-standing strategy for the treatment of metastatic prostate cancer has been to reduce androgenic stimulation of tumor growth by removal of the testes, the primary site of testosterone synthesis. However, a low level of androgenic stimulation may continue, even after castration, by the conversion of adrenal androgens to 5alpha-dihydrotestosterone (DHT) in the prostate tumor cells. Two important enzymes of the androgen biosynthetic pathway are 17alpha-hydroxylase/C17,20-lyase, which regulates an early step in the synthesis of testosterone and other androgens in both the testes and adrenal glands, and 5alpha-reductase, which converts testosterone to the more potent androgen, DHT, in the prostate. We have identified new inhibitors of these enzymes that may be of use in achieving a more complete ablation of androgens in the treatment of metastatic prostate cancer. Three derivatives of androstene were shown to inhibit 17alpha-hydroxylase/C17,20-lyase with potencies 2-20-fold greater than that of ketoconazole, a previously established inhibitor of this enzyme. Derivatives of pregnane and pregnene displayed activities against 5alpha-reductase that were comparable to that of N-(1,1-dimethyl-ethyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-car boxamide. All of the 5alpha-reductase inhibitors were able to at least partially inhibit the mitogenic effect of testosterone in either histocultures of human benign prostatic hypertrophic tissue or in cultures of the LNCaP human prostatic tumor cell line. For these compounds, it appears that this inhibition can be attributed to a reduction of DHT synthesis in these cultures, because no inhibitory effect was observed in DHT-treated cultures, and none of the compounds had a cytotoxic effect. Surprisingly, one of the inhibitors of 17alpha-hydroxylase/C17,20-lyase, 17beta-(4-imidazolyl)-5-pregnen-3beta-ol, was also able to inhibit the mitogenic effect of testosterone in both the histoculture and cell culture assays and had an effect

  11. 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)

  12. Mechanistic relationship between androgen receptor polyglutamine tract truncation and androgen-dependent transcriptional hyperactivity in prostate cancer cells.

    Science.gov (United States)

    Wang, Qianben; Udayakumar, T S; Vasaitis, Tadas S; Brodie, Angela M; Fondell, Joseph D

    2004-04-23

    Androgen receptor (AR) signaling pathways mediate critical events in normal and neoplastic prostate growth. Shortening of the polymorphic N-terminal polyglutamine (poly(Q)) tract of the AR gene leads to transcriptional hyperactivity and has been correlated with an increased risk of prostate cancer. The underlying mechanisms for these effects are poorly understood. We show here that androgen-dependent cellular proliferation and transcription in prostate cancer cells is inversely correlated to the length of the AR poly(Q) region. We further show that AR proteins containing a shortened poly(Q) region functionally respond to lower concentrations of androgens than wild type AR. Whereas DNA binding activity is relatively unaffected by AR poly(Q) variation, we found that ligand binding affinity and the ligand-induced NH(2)- to COOH-terminal intramolecular interaction is enhanced when the poly(Q) region is shortened. Importantly, we show that AR proteins containing a shortened poly(Q) region associate in vivo with higher levels of specific p160 coactivators and components of the SWI/SNF chromatin remodeling complex as compared with the wild type AR. Collectively, our findings suggest that the AR transcriptional hyperactivity associated with shortened poly(Q) length stems from altered ligand-induced conformational changes that enhance coactivator recruitment. PMID:14966121

  13. 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)

  14. 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...

  15. 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

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

    OpenAIRE

    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

    2016-01-01

    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...

  17. 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

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

    International Nuclear Information System (INIS)

    [Methyl-11C]-choline was introduced to image many types of cancer, especially 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 3 d. The cells were then incubated with [Methyl-3H]-choline for 10 min 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 20-70%. 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. The results were interesting in that they showed that flutamide killed the androgen independent prostate cancer cells, PC-3, and the mechanisms responsible for flutamide induced modulation on [Methyl-3H]-choline incorporation are reported. The PC-3 cell proliferation was inhibited by flutamide. In addition, treatment of PC-3 cells with flutamide for 3 d resulted in a buildup of cells in the S phase and [Methyl-3H]-choline incorporation per a cell was found to be decreased in treated as opposed to untreated cells. In conclusion, flutamide inhibits PC-3 cell proliferation by a certain mechanism (unknown) other than

  19. The Efficacy of Neoadjuvant Androgen Deprivation Therapy as a Prostate Volume Reduction before Brachytherapy for Clinically Localized Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Miki,Kenta

    2007-12-01

    Full Text Available From September 2003 to December 2005, 188 patients who visited our hospital and allied institutions for the purpose of prostate brachytherapy were administrated hormonal therapy for volume reductions before brachytherapy. The pretreatment and posttreatment of prostate volume using a transrectal ultrasound volumetric study and the types and duration of hormonal therapy were analyzed. We administered 91 patients with Luteinizing hormone-releasing hormone (LH-RH agonist, 49 patients with anti-androgen (bicaltamide/flutamide, and 48 patients with maximum androgen blockade (MAB. The duration of the hormonal therapy was 1-3 months for 49 patients, 4-6 months for 59 patients, 7-9 months for 40 patients, 10-12 months for 32 patients, and over 13 months for 8 patients. Before the initiation of hormonal therapy, the mean prostate volume was 35.12 ml (11.04-78.71 ml, and the average of prostate volume before and after hormonal therapy was 36.79 ml and 24.79 ml, respectively (a 32.4% reduction. The prostate volume reduction rate was 32.0% for the LH-RH agonist only, 18.1% for the anti-androgen only and 41.2% for the MAB. No statistically significant difference was observed for the duration of hormonal therapy between 3 groups. A three-month course of the neoadjuvant LH-RH agonist indicated a sufficient volume reduction effectiveness for a large prostate volume.

  20. 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...

  1. Expression of androgen receptor and prostate-specific antigen in male breast carcinoma

    International Nuclear Information System (INIS)

    The androgen-regulated proteins prostate-specific antigen (PSA) and prostate-specific acid phosphatase (PSAP) are present in high concentrations in normal prostate and prostatic cancer and are considered to be tissue-specific to prostate. These markers are commonly used to diagnose metastatic prostate carcinoma at various sites including the male breast. However, expression of these two proteins in tumors arising in tissues regulated by androgens such as male breast carcinoma has not been thoroughly evaluated. In this study we analyzed the expression of PSA, PSAP and androgen receptor (AR) by immunohistochemistry in 26 cases of male breast carcinomas and correlated these with the expression of other prognostic markers. AR, PSA and PSAP expression was observed in 81%, 23% and 0% of carcinomas, respectively. Combined expression of AR and PSA was observed in only four tumors. Although the biological significance of PSA expression in male breast carcinomas is not clear, caution should be exercised when it is used as a diagnostic marker of metastatic prostate carcinoma

  2. 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

  3. 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.

  4. 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

  5. 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...

  6. Five-alpha Reductase Inhibitor Influences Expression of Androgen Receptor and HOXB13 in Human Hyperplastic Prostate Tissue

    OpenAIRE

    Chaeyong Jung; Youngwoong Park; Young-Rang Kim; Soo Bang Ryu; Taek Won Kang

    2013-01-01

    Objectives Five-alpha reductase inhibitors (5ARIs) are known as chemopreventive agents in prostate cancer with a risk of high-grade disease. This study evaluated the effects of 5ARI on androgen receptor (AR) and proteins involved in prostate cell growth such as HOXB13 expression in human prostate tissue and LNCaP prostate cancer cells. Materials and Methods We retrospectively selected 21 patients who underwent TURP between March 2007 and February 2010 for previously confirmed BPH by prostate...

  7. 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...

  8. Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention

    OpenAIRE

    Jia, Shidong; Gao, Xueliang; Lee, Sang Hyun; Maira, Sauveur-Michel; Wu, Xiaoqiu; Stack, Edward C.; Signoretti, Sabina; Loda, Massimo; Zhao, Jean J.; Roberts, Thomas M.

    2012-01-01

    Prostate cancer is an ideal target for chemoprevention. To date, chemoprevention clinical trials with 5α-reductase inhibitors (5-ARI) have yielded encouraging yet ultimately confounding results. Using a pre-clinical mouse model of high-grade prostatic intraepithelial neoplasia (HG-PIN) induced by PTEN loss, we observed unprecedented deteriorating effects of androgen deprivation, where surgical castration or MDV3100 treatment accelerated disease progression of the otherwise stable HG-PIN to in...

  9. 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...

  10. 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.)

  11. 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

  12. 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.

  13. Vitamin D3 regulates the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Linda Kelsey

    Full Text Available 1α-25(OH2 vitamin D3 (1-25D, an active hormonal form of Vitamin D3, is a well-known chemopreventive and pro-differentiating agent. It has been shown to inhibit the growth of several prostate cancer cell lines. Gap junctions, formed of proteins called connexins (Cx, are ensembles of cell-cell channels, which permit the exchange of small growth regulatory molecules between adjoining cells. Cell-cell communication mediated by gap junctional channels is an important homeostatic control mechanism for regulating cell growth and differentiation. We have investigated the effect of 1-25D on the formation and degradation of gap junctions in an androgen-responsive prostate cancer cell line, LNCaP, which expresses retrovirally-introduced Cx32. Connexin32 is expressed by the luminal and well-differentiated cells of normal prostate and prostate tumors. Our results document that 1-25D enhances the expression of Cx32 and its subsequent assembly into gap junctions. Our results further show that 1-25D prevents androgen-regulated degradation of Cx32, post-translationally, independent of androgen receptor (AR-mediated signaling. Finally, our findings document that formation of gap junctions sensitizes Cx32-expressing LNCaP cells to the growth inhibitory effects of 1-25D and alters their morphology. These findings suggest that the growth-inhibitory effects of 1-25D in LNCaP cells may be related to its ability to modulate the assembly of Cx32 into gap junctions.

  14. 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

  15. 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.

  16. Dominant-Negative Androgen Receptor Inhibition of Intracrine Androgen-Dependent Growth of Castration-Recurrent Prostate Cancer

    Science.gov (United States)

    Kantor, Boris; Li, Xiangping; Haack, Karin; Moore, Dominic T.; Wilson, Elizabeth M.

    2012-01-01

    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. PMID:22272301

  17. 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.

  18. Vertebral Fractures and Trabecular Microstructure in Men with Prostate Cancer on Androgen Deprivation Therapy

    OpenAIRE

    Greenspan, Susan L.; Wagner, Julie; Joel B. Nelson; Perera, Subashan; Britton, Cynthia; Resnick, Neil M.

    2013-01-01

    Androgen deprivation therapy (ADT), a treatment for prostate cancer, is associated with bone loss and fractures. Dual energy x-ray absorptiometry (DXA) measured bone mineral density does not assess vertebral fractures (VF). High resolution microMRI (HR-MRI) assesses bone microarchitecture and provides structural information.

  19. 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.

  20. 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...

  1. 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

    Anabolic signals such as androgens and the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis play an essential role in the normal development of the prostate but also in its malignant transformation. In this study, we investigated the role of suppressor of cytokine signaling 2 (SOCS2) a...

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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...

  14. 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...

  15. 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...

  16. 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 ...

  17. 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

  18. 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

  19. 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...

  20. Measurement of bone turnover in prostate cancer patients receiving intermittent androgen suppression therapy

    Directory of Open Access Journals (Sweden)

    Gerhard Theyer

    2010-09-01

    Full Text Available Gerhard Theyer1, Stefan Holub2, Ulrike Olszewski3, Gerhard Hamilton31Hospital Kittsee, Kittsee, Burgenland, Austria; 2Department of Urology, Wilhelminenspital, Vienna, Austria; 3Ludwig Boltzmann Society, Vienna, AustriaPurpose: Reports on clinical measurements of bone mineral density (BMD in prostate cancer patients undergoing intermittent androgen suppression therapy (IAS that allows for hormonal recovery between treatment cycles indicate decreased osteoporosis compared to continuous androgen suppression therapy (CAS. In the present study the effect of IAS on bone metabolism by determinations of CrossLaps, a biochemical marker of collagen degradation, were examined. Method: In total 100 IAS treatment cycles of 75 patients with prostate cancer stages ≥ pT2 were studied. Clinical data and monthly laboratory tests (testosterone, prostate-specific antigen; PSA of these patients were monitored together with measurements of C-terminal telopeptide collagen fragments using CrossLaps® ELISA assays. Results: During phases of androgen suppression (AS lasting for 9 months serum testosterone (<1 ng/mL and PSA (<2 ng/mL levels were reversibly reduced, indicating partial growth arrest and apoptotic regression of the prostatic tumors. Serum CrossLaps concentrations peaked at the last 2 months of the AS phases (0.91 ± 0.25 µg/L; mean ± SEM and were reduced below initial values (0.21 ± 0.43 versus baseline of 0.43 ± 0.06 µg/L during therapy cessation periods until tumor progression-related increases. Conclusion: Measurements of the serum concentration of CrossLaps in prostate cancer patients receiving IAS indicated that treatment cessation phases rapidly reversed increased bone degradation associated with AS phases, in strong agreement with the clinical observations reporting reduced loss of BMD in IAS when compared to CAS. In terms of clinical outcomes, IAS seems to be as effective as CAS while showing reduced side effects, as demonstrated here by the

  1. Activation of Beta-Catenin Signaling in Androgen Receptor–Negative Prostate Cancer Cells

    Science.gov (United States)

    Wan, Xinhai; Liu, Jie; Lu, Jing-Fang; Tzelepi, Vassiliki; Yang, Jun; Starbuck, Michael W.; Diao, Lixia; Wang, Jing; Efstathiou, Eleni; Vazquez, Elba S.; Troncoso, Patricia; Maity, Sankar N.; Navone, Nora M.

    2012-01-01

    Purpose To study Wnt/beta-catenin in castrate-resistant prostate cancer (CRPC) and understand its function independently of the beta-catenin–androgen receptor (AR) interaction. Experimental Design We performed beta-catenin immunocytochemical analysis, evaluated TOP-flash reporter activity (a reporter of beta-catenin–mediated transcription), and sequenced the beta-catenin gene in MDA PCa 118a, MDA PCa 118b, MDA PCa 2b, and PC-3 prostate cancer (PCa) cells. We knocked down beta-catenin in AR-negative MDA PCa 118b cells and performed comparative gene-array analysis. We also immunohistochemically analyzed beta-catenin and AR in 27 bone metastases of human CRPCs. Results Beta-catenin nuclear accumulation and TOP-flash reporter activity were high in MDA PCa 118b but not in MDA PCa 2b or PC-3 cells. MDA PCa 118a and 118b cells carry a mutated beta-catenin at codon 32 (D32G). Ten genes were expressed differently (false discovery rate, 0.05) in MDA PCa 118b cells with downregulated beta-catenin. One such gene, hyaluronan synthase 2 (HAS2), synthesizes hyaluronan, a core component of the extracellular matrix. We confirmed HAS2 upregulation in PC-3 cells transfected with D32G-mutant beta-catenin. Finally, we found nuclear localization of beta-catenin in 10 of 27 human tissue specimens; this localization was inversely associated with AR expression (P = 0.056, Fisher’s exact test), suggesting that reduced AR expression enables Wnt/beta-catenin signaling. Conclusion We identified a previously unknown downstream target of beta-catenin, HAS2, in PCa, and found that high beta-catenin nuclear localization and low or no AR expression may define a subpopulation of men with bone-metastatic PCa. These findings may guide physicians in managing these patients. PMID:22298898

  2. 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.

  3. 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

  4. 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.

  5. Gene expression changes in rat prostate after activation or blocking of the androgen and estrogen receptor

    DEFF Research Database (Denmark)

    Nellemann, Christine Lydia; Dalgaard, Majken; Holst, Bjørn;

    2005-01-01

    Several endpoints of different molecular complexity were studied in the Hershberger assay in order to evaluate the specificity and suitability of this test as a broad screening model. Androgen and estrogen receptors were activated or blocked, and expression of typical estrogen- or androgen...... anti-estrogen, ICI 182780, only affected ODC expression. Therefore, estrogenic or anti-estrogenic compounds would not be expected to seriously affect the outcome of a Hershberger test. However, EB given alone to castrated rats resulted in various effects. EB increased seminal vesicle weight, an effect...... reversed by ICI 182780, and affected TRPM-2, PBP C3, ODC, IGF-1, AR, and ERa mRNA levels. AR expression in the prostate seemed to be under regulation of both estrogens and androgens, as ICI 182780 inhibited the testosterone-induced AR expression, and flutamide inhibited the EB-induced AR expression. These...

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse.

    Science.gov (United States)

    Pu, Yang; Xu, Meng; Liang, Yong; Yang, Kaiting; Guo, Yajun; Yang, Xuanming; Fu, Yang-Xin

    2016-04-01

    Surgical and medical androgen deprivation therapy (ADT) is a cornerstone for prostate cancer treatment, but relapse usually occurs. We herein show that orchiectomy synergizes with immunotherapy, whereas the more widely used treatment of medical ADT involving androgen receptor (AR) antagonists suppresses immunotherapy. Furthermore, we observed that the use of medical ADT could unexpectedly impair the adaptive immune responses through interference with initial T cell priming rather than in the reactivation or expansion phases. Mechanistically, we have revealed that inadvertent immunosuppression might be potentially mediated by a receptor shared with γ-aminobutyric acid. Our data demonstrate that the timing and dosing of antiandrogens are critical to maximizing the antitumor effects of combination therapy. This study highlights an underappreciated mechanism of AR antagonist-mediated immunosuppression and provides a new strategy to enhance immune response and prevent the relapse of advanced prostate cancer. PMID:27053771

  11. 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. PMID:26760770

  12. 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.

  13. 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

  14. 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...

  15. Pterostilbene-Isothiocyanate Conjugate Suppresses Growth of Prostate Cancer Cells Irrespective of Androgen Receptor Status

    OpenAIRE

    Nikhil, Kumar; Sharan, Shruti; Chakraborty, Ajanta; Roy, Partha

    2014-01-01

    Chemotherapy and anti-hormonal therapies are the most common treatments for non-organ-confined prostate cancer (PCa). However, the effectiveness of these therapies is limited, thus necessitating the development of alternative approaches. The present study focused on analyzing the role of pterostilbene (PTER)-isothiocyanate (ITC) conjugate – a novel class of hybrid compound synthesized by appending an ITC moiety on PTER backbone – in regulating the functions of androgen receptor (AR), thereby ...

  16. 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

  17. 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...

  18. 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...

  19. 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.

  20. Steroid-induced androgen receptor–oestradiol receptor β–Src complex triggers prostate cancer cell proliferation

    OpenAIRE

    Migliaccio, Antimo; Castoria, Gabriella; Di Domenico, Marina; de Falco, Antonietta; Bilancio, Antonio; Lombardi, Maria; Barone, Maria Vittoria; Ametrano, Donatella; Zannini, Maria Stella; Abbondanza, Ciro; Auricchio, Ferdinando

    2000-01-01

    Treatment of human prostate carcinoma-derived LNCaP cells with androgen or oestradiol triggers simultaneous association of androgen receptor and oestradiol receptor β with Src, activates the Src/Raf-1/Erk-2 pathway and stimulates cell proliferation. Surprisingly, either androgen or oestradiol action on each of these steps is inhibited by both anti-androgens and anti-oestrogens. Similar findings for oestradiol receptor α were observed in MCF-7 or T47D cells stimulated by either oestradiol or a...

  1. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.

    Science.gov (United States)

    Weischenfeldt, Joachim; Simon, Ronald; Feuerbach, Lars; Schlangen, Karin; Weichenhan, Dieter; Minner, Sarah; Wuttig, Daniela; Warnatz, Hans-Jörg; Stehr, Henning; Rausch, Tobias; Jäger, Natalie; Gu, Lei; Bogatyrova, Olga; Stütz, Adrian M; Claus, Rainer; Eils, Jürgen; Eils, Roland; Gerhäuser, Clarissa; Huang, Po-Hsien; Hutter, Barbara; Kabbe, Rolf; Lawerenz, Christian; Radomski, Sylwester; Bartholomae, Cynthia C; Fälth, Maria; Gade, Stephan; Schmidt, Manfred; Amschler, Nina; Haß, Thomas; Galal, Rami; Gjoni, Jovisa; Kuner, Ruprecht; Baer, Constance; Masser, Sawinee; von Kalle, Christof; Zichner, Thomas; Benes, Vladimir; Raeder, Benjamin; Mader, Malte; Amstislavskiy, Vyacheslav; Avci, Meryem; Lehrach, Hans; Parkhomchuk, Dmitri; Sultan, Marc; Burkhardt, Lia; Graefen, Markus; Huland, Hartwig; Kluth, Martina; Krohn, Antje; Sirma, Hüseyin; Stumm, Laura; Steurer, Stefan; Grupp, Katharina; Sültmann, Holger; Sauter, Guido; Plass, Christoph; Brors, Benedikt; Yaspo, Marie-Laure; Korbel, Jan O; Schlomm, Thorsten

    2013-02-11

    Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic "androgen-type" pathomechanism in EO-PCA. PMID:23410972

  2. 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.

  3. 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

  4. Redirecting abiraterone metabolism to fine-tune prostate cancer anti-androgen therapy.

    Science.gov (United States)

    Li, Zhenfei; Alyamani, Mohammad; Li, Jianneng; Rogacki, Kevin; Abazeed, Mohamed; Upadhyay, Sunil K; Balk, Steven P; Taplin, Mary-Ellen; Auchus, Richard J; Sharifi, Nima

    2016-05-26

    Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy. PMID:27225130

  5. 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。

  6. 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

  7. Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

    OpenAIRE

    Lee C; Kilgour Andrea; Lau YK

    2012-01-01

    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 e...

  8. 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...

  9. 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

  10. 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

  11. 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.

  12. Quantitative Time-Resolved Fluorescence Imaging of Androgen Receptor and Prostate-Specific Antigen in Prostate Tissue Sections.

    Science.gov (United States)

    Krzyzanowska, Agnieszka; Lippolis, Giuseppe; Helczynski, Leszek; Anand, Aseem; Peltola, Mari; Pettersson, Kim; Lilja, Hans; Bjartell, Anders

    2016-05-01

    Androgen receptor (AR) and prostate-specific antigen (PSA) are expressed in the prostate and are involved in prostate cancer (PCa). The aim of this study was to develop reliable protocols for reproducible quantification of AR and PSA in benign and malignant prostate tissue using time-resolved fluorescence (TRF) imaging techniques. AR and PSA were detected with TRF in tissue microarrays from 91 PCa patients. p63/ alpha-methylacyl-CoA racemase (AMACR) staining on consecutive sections was used to categorize tissue areas as benign or cancerous. Automated image analysis was used to quantify staining intensity. AR intensity was significantly higher in AMACR+ and lower in AMACR- cancer areas as compared with benign epithelium. The PSA intensity was significantly lower in cancer areas, particularly in AMACR- glands. The AR/PSA ratio varied significantly in the AMACR+ tumor cells as compared with benign glands. There was a trend of more rapid disease progression in patients with higher AR/PSA ratios in the AMACR- areas. This study demonstrates the feasibility of developing reproducible protocols for TRF imaging and automated image analysis to study the expression of AR and PSA in benign and malignant prostate. It also highlighted the differences in AR and PSA protein expression within AMACR- and AMACR+ cancer regions. PMID:27026295

  13. 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.

  14. 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

  15. Maspin mediates the gemcitabine sensitivity of hormone-independent prostate cancer.

    Science.gov (United States)

    Huang, Chien-Yu; Chang, Yu-Jia; Luo, Sheng-Dean; Uyanga, Batzorig; Lin, Feng-Yen; Tai, Cheng-Jeng; Huang, Ming-Te

    2016-03-01

    Androgen deprivation therapy has constituted the main treatment for prostate cancer; however, tumors ultimately progress to hormone-independent prostate cancer (HIPC), and suitable therapeutic strategies for HIPC are not available. Maspin, which is also known as mammary serine protease inhibitor, has been suggested to be a valuable focus for targeted cancer therapy. Specifically, maspin has been shown to be upregulated after androgen ablation therapy. Gemcitabine is used as a first-line therapy for metastatic castration-resistant prostate cancer, but its disease control rate is low. Furthermore, the role of maspin in the therapeutic efficacy of gemcitabine for HIPC remains unclear. The expression levels of maspin in PC-3 and DU145 cells were determined by real-time PCR and Western blotting. Furthermore, the expression of maspin was silenced using shRNA technology to generate maspin-KD cells. The cytotoxicity of gemcitabine to prostate cancer cells was assessed using 3-[4,5-dimethylthiazol-2-yl]-3,5-diphenyl tetrazolium bromide (MTT) assays, whereas flow cytometry analyses and annexin V-propidium iodide (PI) apoptosis assays were used to assess the ability of gemcitabine to induce apoptosis in maspin-KD and control cells. Additionally, the expression patterns of anti-apoptosis proteins (myeloid cell leukemia 1 (Mcl-1) and B cell lymphoma 2 (Bcl-2)) and pro-apoptosis proteins (Bcl-2-associated death promoter (Bad) and Bcl-2-associated X protein (Bax)) were determined by Western blotting. In this study, PC-3 cells were more resistant to gemcitabine administration than DU145 cells, which correlated with the higher expression levels of maspin observed in PC-3 cells. Furthermore, maspin knockdown enhanced gemcitabine-induced cell death, as evidenced by the increased number of apoptotic cells. Gemcitabine treatment upregulated the levels of anti-apoptosis proteins (Mcl-2 and Bcl-2) in both scrambled control and maspin-KD cells; however, the fold changes in Mcl-1 and Bcl-2

  16. Potent anti-prostate cancer agents derived from a novel androgen receptor down-regulating agent.

    Science.gov (United States)

    Purushottamachar, Puranik; Khandelwal, Aakanksha; Vasaitis, Tadas S; Bruno, Robert D; Gediya, Lalji K; Njar, Vincent C O

    2008-04-01

    The search for novel androgen receptor (AR) down-regulating agents by catalyst HipHop pharmacophore modeling led to the discovery of some lead molecules. Unexpectedly, the effect of these leads on human prostate cancer LNCaP cell viability did not correlate with the ability of the compounds to cause down-regulation of AR protein expression. Through rational synthetic optimization of the lead compound (BTB01434), we have discovered a series of novel substituted diaryl molecules as potent anti-prostate cancer agents. Some compounds (1-6) were shown to be extremely potent inhibitors of LNCaP cell viability with GI(50) values in the nanomolar range (1.45-83 nM). The most potent compound (4-methylphenyl)[(4-methylphenyl)sulfonyl]amine (5) with a GI(50) value of 1.45 nM is 27,000 times more potent than our lead compound BTB01434 (GI(50)=39.8 microM). In addition, some of the compounds exhibited modest anti-androgenic activities and one was also a potent inhibitor (GI(50)=850 nM) of PC-3 (AR-null) cell growth. A clear structure-activity relationship (SAR) has been established for activity against LNCaP cells, where potent molecules possess two substituted/unsubstituted aromatic rings connected through a sulfonamide linker. These novel compounds are strong candidates for development for the treatment of hormone-sensitive and importantly hormone-refractory prostate cancers in humans. PMID:18316193

  17. 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

  18. 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.

  19. 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

  20. 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

  1. 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.

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

    International Nuclear Information System (INIS)

    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

  3. 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

  4. 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.

  5. 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.

  6. 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......-sectional study at a large university hospital. A specific questionnaire was developed based on current literature, clinical experience and a pilot phase of the study. The primary endpoint was preferred treatment frequency. Secondary outcome measures included reasons for preferred treatment frequency, treatment...... satisfaction and side-effects. Overall, 238 men receiving ADT for prostate cancer were presented with the questionnaire between September 2011 and May 2012. Descriptive statistics, the chi-squared test and multiple regression were used for analyses. RESULTS: In total, 176 questionnaires (74%) were available...

  7. 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

    -extensor muscle strength (one repetition maximum), fat percentage, and maximal oxygen uptake (VO2max ). Mean heart rate during training was 137.7 (standard deviation 13.7) bpm or 84.6 (3.9)% HRmax. In FG, LBM increased by 0.5 kg [95% confidence interval (CI) 0.1-0.9; P = 0.02] with no change in CON (mean group......Androgen deprivation therapy (ADT) remains a cornerstone in the management of patients with prostate cancer (PCa) despite adverse effects on body composition and functional parameters. We compared the effects of football training with standard care in PCa patients managed with ADT (> 6 months.......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....

  8. Androgen receptor variant-7: an important predictive biomarker in castrate resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Oliver Sartor

    2015-06-01

    Full Text Available The recent manuscript in New England Journal of Medicine by Antonarakis et al. [1] has important clinical implications. This study evaluates mRNA expression of a particular androgen receptor splice variant-7 (AR-V7, in circulating tumor cells (CTCs from metastatic castrate-resistant prostate cancer (mCRPC patients receiving enzalutamide or abiraterone. The findings were striking, none of the 18 patients with detectable AR-V7 in CTCs had prostate-specific antigen (PSA responses. Further, the median time to PSA progression after enzalutamide or abiraterone treatment was only 1.3-1.4 months in AR-V7-positive patients as compared to 5.3-6.1 months in AR-V7 negative patients. AR-V7 in CTCs was also associated with shorter survival.

  9. Adverse Effects of Androgen Deprivation Therapy: Defining the Problem and Promoting Health Among Men with Prostate Cancer

    OpenAIRE

    Saylor, Philip J; Smith, Matthew R.

    2010-01-01

    Androgen deprivation therapy (ADT) plays a central role in the management of men with locally advanced, recurrent, and metastatic prostate cancer. Because most men diagnosed with prostate cancer will die of something other than their cancer, treatment-related adverse effects are highly relevant to their long-term health. Benefits of ADT in each clinical setting must be weighed against ADT-related adverse effects. ADT is detrimental to several metabolic end points and to bone health. ADT has b...

  10. 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

  11. 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.

  12. 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

  13. 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

  14. 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...

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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)

  20. 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.; Haukaas, S.; Henriksson, P.; Johansson, R.; Klarskov, P.; Rasmussen, F.; Varenhorst, E.; Viitanen, J.; Hedlund, Per Olov; Damber, Jan-Erik; Hagerman, Inger; Haukaas, Svein; Henriksson, Peter; Iversen, Peter; Johansson, Robert; Klarskov, Ole Peter; Lundbeck, Finn; Rasmussen, Finn; Varenhorst, Eberhard; Viitanen, Jouko

    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, esp...

  1. Influence of Age on Incident Diabetes and Cardiovascular Disease in Prostate Cancer Survivors Receiving Androgen Deprivation Therapy

    Science.gov (United States)

    Morgans, Alicia K.; Fan, Kang-Hsien; Koyama, Tatsuki; Albertsen, Peter C.; Goodman, Michael; Hamilton, Ann S.; Hoffman, Richard M.; Stanford, Janet L.; Stroup, Antoinette M.; Resnick, Matthew J.; Barocas, Daniel A.; Penson, David F.

    2015-01-01

    Purpose Observational data suggest that androgen deprivation therapy increases the risk of diabetes and cardiovascular disease. Using data from the population based PCOS we evaluated whether age at diagnosis and comorbidity impact the association of androgen deprivation therapy with incident diabetes and cardiovascular disease. Materials and Methods We identified men with nonmetastatic prostate cancer diagnosed from 1994 to 1995 who were followed through 2009 to 2010. We used multivariable logistic regression models to assess the relationship of androgen deprivation therapy exposure (2 or fewer years, greater than 2 years or none) with incident diabetes and cardiovascular disease, adjusting for age at diagnosis, race, stage and comorbidity. Results Of 3,526 eligible study participants 2,985 without diabetes and 3,112 without cardiovascular disease comprised the cohorts at risk. Androgen deprivation therapy was not associated with an increased risk of diabetes or cardiovascular disease in men diagnosed with prostate cancer before age 70 years. Prolonged androgen deprivation therapy and increasing age at diagnosis in older men was associated with an increased risk of diabetes (at age 76 years OR 2.1, 95% CI 1.0–4.4) and cardiovascular disease (at age 74 years OR 1.9, 95% CI 1.0–3.5). Men with comorbidities were at greater risk for diabetes (OR 4.3, 95% CI 2.3–7.9) and cardiovascular disease (OR 8.1, 95% CI 4.3–15.5) than men without comorbidities. Conclusions Prolonged androgen deprivation therapy exposure increases the risk of cardiovascular disease and diabetes in men diagnosed with prostate cancer who are older than approximately 75 years, especially those with other comorbidities. Older men who receive prolonged androgen deprivation therapy should be closely monitored for diabetes and cardiovascular disease. PMID:25451829

  2. 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

  3. 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.

  4. Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments.

    Science.gov (United States)

    Vasaitis, Tadas S; Njar, Vincent C O

    2010-04-01

    The beneficial effect of androgen ablation has been well established in prostate cancer therapy. Despite the initial response, patients typically relapse with a more aggressive form described as castration-resistant prostate cancer (CRCP), driven by continued androgen receptor (AR) signaling. This review details the current state of anti-androgen therapy, mainly for CRPC, with major emphasis on the most potent and promising compounds under development. Anti-androgen failure has been linked to elevated AR expression, increased expression of coactivator proteins, AR mutations, ligand-independent AR activation and persistent intraprostatic androgens. MDV3100, BMS-641988 and VN/124-1 were developed to overcome these mechanisms. In CRCP, prostate cancer cells still rely on intracellular androgens and, to a greater extent, on active AR for growth and survival. Therefore, potent anti-androgens that efficiently disrupt the functions (signaling) of AR are envisioned to be effective drugs for all types of prostate cancers. PMID:21426013

  5. 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

  6. 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.

  7. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation.

    Science.gov (United States)

    Migliaccio, A; Castoria, G; Di Domenico, M; de Falco, A; Bilancio, A; Lombardi, M; Barone, M V; Ametrano, D; Zannini, M S; Abbondanza, C; Auricchio, F

    2000-10-16

    Treatment of human prostate carcinoma-derived LNCaP cells with androgen or oestradiol triggers simultaneous association of androgen receptor and oestradiol receptor beta with Src, activates the Src/Raf-1/Erk-2 pathway and stimulates cell proliferation. Surprisingly, either androgen or oestradiol action on each of these steps is inhibited by both anti-androgens and anti-oestrogens. Similar findings for oestradiol receptor alpha were observed in MCF-7 or T47D cells stimulated by either oestradiol or androgens. Microinjection of LNCaP, MCF-7 and T47D cells with SrcK(-) abolishes steroid-stimulated S-phase entry. Data from transfected Cos cells confirm and extend the findings from these cells. Hormone-stimulated Src interaction with the androgen receptor and oestradiol receptor alpha or beta is detected using glutathione S:-transferase fusion constructs. Src SH2 interacts with phosphotyrosine 537 of oestradiol receptor alpha and the Src SH3 domain with a proline-rich stretch of the androgen receptor. The role of this phosphotyrosine is stressed by its requirement for association of oestradiol receptor alpha with Src and consequent activation of Src in intact Cos cells. PMID:11032808

  8. Steroid-induced androgen receptor–oestradiol receptor β–Src complex triggers prostate cancer cell proliferation

    Science.gov (United States)

    Migliaccio, Antimo; Castoria, Gabriella; Di Domenico, Marina; de Falco, Antonietta; Bilancio, Antonio; Lombardi, Maria; Barone, Maria Vittoria; Ametrano, Donatella; Zannini, Maria Stella; Abbondanza, Ciro; Auricchio, Ferdinando

    2000-01-01

    Treatment of human prostate carcinoma-derived LNCaP cells with androgen or oestradiol triggers simultaneous association of androgen receptor and oestradiol receptor β with Src, activates the Src/Raf-1/Erk-2 pathway and stimulates cell proliferation. Surprisingly, either androgen or oestradiol action on each of these steps is inhibited by both anti-androgens and anti-oestrogens. Similar findings for oestradiol receptor α were observed in MCF-7 or T47D cells stimulated by either oestradiol or androgens. Microinjection of LNCaP, MCF-7 and T47D cells with SrcK– abolishes steroid-stimulated S-phase entry. Data from transfected Cos cells confirm and extend the findings from these cells. Hormone-stimulated Src interaction with the androgen receptor and oestradiol receptor α or β is detected using glutathione S-transferase fusion constructs. Src SH2 interacts with phosphotyrosine 537 of oestradiol receptor α and the Src SH3 domain with a proline-rich stretch of the androgen receptor. The role of this phosphotyrosine is stressed by its requirement for association of oestradiol receptor α with Src and consequent activation of Src in intact Cos cells. PMID:11032808

  9. 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.

  10. Iodine-125 Nilutamide as Novel Radio-therapeutic Ligand for Androgen Receptor in Prostate Cancer

    International Nuclear Information System (INIS)

    Nilutamide is potent anti-androgen that is used in patients with metastatic prostate carcinoma. The labeling of nilutamide with iodine radioisotopes give an advantage to localize these radionuclides in prostate for imaging and/or therapy depending on the radionuclide used. During this study, nilutamide was labeled successfully with iodine-125 in a neutral ph medium using chloramine-T as oxidizing agent and the radiochemical yield obtained was greater than 96%. The biodistribution of the iodine-125-nilutamide in normal mice indicated the ability of the tracer to bind with specific receptors in prostate and other male organs with 3.5 % at 4 hours post injection. The clearance of the tracer from the blood pool was slow and equal to 40% of the initial blood uptake at 4 hours post injection. The in vivo stability of the tracer was established by the absence of the thyroid uptake. The competition binding was achieved via 1M injection of testosterone and IV injection of non-labeled nilutamide 2 hours before the administration of the tracer. The results referred to a significant reduction in the uptake of the tracer by the prior administration of testosterone and non-labeled nilutamide by 60% and 30%, respectively at 4 hours post injection

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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

  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. 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.

  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. 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

  2. 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...

  3. Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells.

    Science.gov (United States)

    Kashiwagi, Eiji; Shiota, Masaki; Yokomizo, Akira; Itsumi, Momoe; Inokuchi, Junichi; Uchiumi, Takeshi; Naito, Seiji

    2013-06-01

    Although numerous epidemiological studies show aspirin to reduce risk of prostate cancer, the mechanism of this effect is unclear. Here, we first confirmed that aspirin downregulated androgen receptor (AR) and prostate-specific antigen in prostate cancer cells. We also found that aspirin upregulated prostaglandin receptor subtype EP3 but not EP2 or EP4. The EP3 antagonist L798106 and EP3 knockdown increased AR expression and cell proliferation, whereas the EP3 agonist sulprostone decreased them, indicating that EP3 affects AR expression. Additionally, EP3 (PTGER3) transcript levels were significantly decreased in human prostate cancer tissues compared with those in normal human prostate tissues, suggesting that EP3 is important to prostate carcinogenesis. Decreased EP3 expression was also seen in castration-resistant subtype CxR cells compared with parental LNCaP cells. Finally, we found that aspirin and EP3 modulators affected prostate cancer cell growth. Taken together, aspirin suppressed LNCaP cell proliferation via EP3 signaling activation; EP3 downregulation contributed to prostate carcinogenesis and to progression from androgen-dependent prostate cancer to castration-resistant prostate cancer by regulating AR expression. In conclusion, cyclooxygenases and EP3 may represent attractive therapeutic molecular targets in androgen-dependent prostate cancer. PMID:23493387

  4. 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.

  5. Short-term Androgen-Deprivation Therapy Improves Prostate Cancer-Specific Mortality in Intermediate-Risk Prostate Cancer Patients Undergoing Dose-Escalated External Beam Radiation Therapy

    International Nuclear Information System (INIS)

    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

  6. 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

  7. 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)

  8. 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

  9. Antiinflammatory effect of androgen receptor activation in human benign prostatic hyperplasia cells.

    Science.gov (United States)

    Vignozzi, Linda; Cellai, Ilaria; Santi, Raffaella; Lombardelli, Letizia; Morelli, Annamaria; Comeglio, Paolo; Filippi, Sandra; Logiodice, Federica; Carini, Marco; Nesi, Gabriella; Gacci, Mauro; Piccinni, Marie-Pierre; Adorini, Luciano; Maggi, Mario

    2012-07-01

    Progression of benign prostatic hyperplasia (BPH) involves chronic inflammation and immune dysregulation. Preclinical studies have demonstrated that prostate inflammation and tissue remodeling are exacerbated by hypogonadism and prevented by testosterone supplementation. We now investigated whether, in humans, hypogonadism was associated with more severe BPH inflammation and the in vitro effect of the selective androgen receptor agonist dihydrotestosterone (DHT) on cultures of stromal cells derived from BPH patients (hBPH). Histological analysis of inflammatory infiltrates in prostatectomy specimens from a cohort of BPH patients and correlation with serum testosterone level was performed. Even after adjusting for confounding factors, hypogonadism was associated with a fivefold increased risk of intraprostatic inflammation, which was also more severe than that observed in eugonadal BPH patients. Triggering hBPH cells by inflammatory stimuli (tumor necrosis factor α, lipopolysaccharide, or CD4(+)T cells) induced abundant secretion of inflammatory/growth factors (interleukin 6 (IL6), IL8, and basic fibroblast growth factor (bFGF)). Co-culture of CD4(+)T cells with hBPH cells induced secretion of Th1 inducer (IL12), Th1-recruiting chemokine (interferon γ inducible protein 10, IP10), and Th2 (IL9)- and Th17 (IL17)-specific cytokines. Pretreatment with DHT inhibited NF-κB activation and suppressed secretion of several inflammatory/growth factors, with the most pronounced effects on IL8, IL6, and bFGF. Reduced inflammatory cytokine production by T-cells, an increase in IL10, and a significant reduction of T cells proliferation suggested that DHT exerted a broad anti inflammatory effect on testosterone cells [corrected]. In conclusion, our data demonstrate that DHT exerts an immune regulatory role on human prostatic stromal cells, inhibiting their potential to actively induce and/or sustain autoimmune and inflammatory responses. PMID:22562653

  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. 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.

  16. 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

  17. Characterization of 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine at androgen receptor: mechanistic support for its role in prostate cancer

    OpenAIRE

    Glass-Holmes, Mashunté; Aguilar, Byron J.; Richard D. Gragg; DARLING-REED, SELINA; GOODMAN, CARL B.

    2014-01-01

    2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP) is a dietary mutagenic carcinogen that has been shown not only to induce the formation of DNA adducts, but is capable of inducing tumors in the colon, mammary, and prostate glands. The normal development and maturation of the prostate gland, as well as early progression of prostate cancer, is dependent on androgens acting on the androgen receptor (AR). The actual mechanism by which PhIP interacts with our biological system and its potentia...

  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. Androgen deprivation therapy did not increase the risk of Alzheimer's and Parkinson's disease in patients with prostate cancer.

    Science.gov (United States)

    Chung, S D; Lin, H C; Tsai, M C; Kao, L T; Huang, C Y; Chen, K C

    2016-05-01

    Androgen deprivation therapy (ADT) has been the standard treatment for advanced prostate cancer for many decades. Although potential adverse effects of ADT have been reported, there are no empirical studies investigating the association between ADT and Alzheimer's disease. Therefore, this retrospective cohort study explored the relationship between the use of ADT and the subsequent risk of Alzheimer's disease in men with prostate cancer using a population-based database. We retrieved data from the "Taiwan Longitudinal Health Insurance Database 2000." The study included 1335 patients with prostate cancer and 4005 age-matched comparison patients without prostate malignancy. We then individually tracked each patient (n = 5340) for a 5-year period to discriminate those who subsequently received a diagnosis of Alzheimer's disease. The Cox proportional hazard regression showed that the hazard ratio (HR) for Alzheimer's disease during the 5-year follow-up period for prostate cancer patients was 1.71 (95% confidence interval (CI) = 0.90~3.25) over that of comparison patients. We further analyzed the hazard ratio for Alzheimer's disease and Parkinson's disease between prostate cancer patients who did and those who did not receive ADT, but we failed to observe a significant difference in the hazard ratio for both diseases during the 5-year follow-up period (adjusted HR = 1.76, 95% CI = 0.55~5.62, and HR = 1.13, 95% CI = 0.58~2.20, respectively). In conclusion, this study demonstrated that the use of androgen deprivation therapy in patients with prostate cancer was not associated with a higher risk of Alzheimer's and Parkinson's disease during the follow-up period. PMID:27062333

  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. 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

  2. Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB

    OpenAIRE

    Muro, Yusuke; Kosaka, Takeo; Mizuno, Ryuichi; Ohashi, Toshio; Shigematsu, Naoyuki; Oya, Mototsugu

    2015-01-01

    We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 y...

  3. Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB.

    Science.gov (United States)

    Muro, Yusuke; Kosaka, Takeo; Mizuno, Ryuichi; Ohashi, Toshio; Shigematsu, Naoyuki; Oya, Mototsugu

    2015-01-01

    We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 year-old prostate cancer patient who became eligible to receive brachytherapy after dutasteride (0.5 mg daily) was added to CAB and prostate volume reduction of 57% was achieved. PMID:26069888

  4. 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; Dejgaard, Thomas Engel; Thomsen, Carsten; Iversen, Peter; Brasso, Klaus; Mikines, Kari J; van Hall, Gerrit; Lindegaard, Birgitte; Solomon, Thomas; Pedersen, Bente K

    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 men...... undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry 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...

  5. 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

  6. Five-alpha Reductase Inhibitor Influences Expression of Androgen Receptor and HOXB13 in Human Hyperplastic Prostate Tissue

    Directory of Open Access Journals (Sweden)

    Chaeyong Jung

    2013-12-01

    Full Text Available Objectives Five-alpha reductase inhibitors (5ARIs are known as chemopreventive agents in prostate cancer with a risk of high-grade disease. This study evaluated the effects of 5ARI on androgen receptor (AR and proteins involved in prostate cell growth such as HOXB13 expression in human prostate tissue and LNCaP prostate cancer cells. Materials and Methods We retrospectively selected 21 patients who underwent TURP between March 2007 and February 2010 for previously confirmed BPH by prostate biopsy. They were grouped into control (group 1, n = 9 and 5ARI treatment (group 2, n = 12 before TURP. AR and HOXB13 expression in prostate tissue was evaluated by immunohistochemical staining. We tested the effect of 5ARI on the expression of AR, prostate specific antigen (PSA and HOXB13 in LNCaP cells. Cells were assessed by Western blot analysis, MTT in vitro proliferation assay, and ELISA. Results: Group 2 showed stronger reactivity for AR and HOXB13 than those of the group 1. MTT assay showed death of LNCaP cells at 25uM of 5ARI. At the same time, ELISA assay for PSA showed that 5ARI inhibited secretion of PSA in LNCaP cells. Western blot analysis showed that 5ARI did not greatly alter AR expression but it stimulated the expression of HOXB13. Conclusions These results demonstrated that 5ARI influences AR and HOXB13 expression in both LNCaP cells and human prostate tissue. In order to use 5ARI in chemoprevention of prostate cancer, we still need to clarify the influence of 5ARI in ARs and oncogenic proteins and its regulation pathway.

  7. 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.

  8. Obesity and the Odds of Weight Gain following Androgen Deprivation Therapy for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    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.

  9. 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) and density, BTMs and postural balance. RESULTS: In the last part of the 12 weeks, FTG performed 194 ± 41 accelerations and 296 ± 65 decelerations at >0.6 m/s/s and covered a distance of 905 ± 297 m at speeds >6 km/h and 2646 ± 705 m per training session. Analysis of baseline-to-12-week change...

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. 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.

  16. Apoptotic Death of Prostate Cancer Cells by a Gonadotropin-Releasing Hormone-II Antagonist

    OpenAIRE

    Park, Sumi; Han, Ji Man; Cheon, Jun; Hwang, Jong-Ik; Seong, Jae Young

    2014-01-01

    Gonadotropin-releasing hormone-I (GnRH-I) has attracted strong attention as a hormonal therapeutic tool, particularly for androgen-dependent prostate cancer patients. However, the androgen-independency of the cancer in advanced stages has spurred researchers to look for new medical treatments. In previous reports, we developed the GnRH-II antagonist Trp-1 to inhibit proliferation and stimulate the autophagic death of various prostate cancer cells, including androgen-independent cells. We furt...

  17. [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

  18. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer

    DEFF Research Database (Denmark)

    Denmeade, Samuel R; Jakobsen, Carsten M; Janssen, Samuel;

    2003-01-01

    Standard anti-proliferative chemotherapy is relatively ineffective against slowly proliferating androgen-independent prostate cancer cells within metastatic sites. In contrast, the lipophilic cytotoxin thapsigargin, which causes apoptosis by disrupting intracellular free Ca2+ levels, is effective...

  19. Vascular responses to radiotherapy and androgen-deprivation therapy in experimental prostate cancer

    International Nuclear Information System (INIS)

    Radiotherapy (RT) and androgen-deprivation therapy (ADT) are standard treatments for advanced prostate cancer (PC). Tumor vascularization is recognized as an important physiological feature likely to impact on both RT and ADT response, and this study therefore aimed to characterize the vascular responses to RT and ADT in experimental PC. Using mice implanted with CWR22 PC xenografts, vascular responses to RT and ADT by castration were visualized in vivo by DCE MRI, before contrast-enhancement curves were analyzed both semi-quantitatively and by pharmacokinetic modeling. Extracted image parameters were correlated to the results from ex vivo quantitative fluorescent immunohistochemical analysis (qIHC) of tumor vascularization (9 F1), perfusion (Hoechst 33342), and hypoxia (pimonidazole), performed on tissue sections made from tumors excised directly after DCE MRI. Compared to untreated (Ctrl) tumors, an improved and highly functional vascularization was detected in androgen-deprived (AD) tumors, reflected by increases in DCE MRI parameters and by increased number of vessels (VN), vessel density (VD), and vessel area fraction (VF) from qIHC. Although total hypoxic fractions (HF) did not change, estimated acute hypoxia scores (AHS) – the proportion of hypoxia staining within 50 μm from perfusion staining – were increased in AD tumors compared to in Ctrl tumors. Five to six months after ADT renewed castration-resistant (CR) tumor growth appeared with an even further enhanced tumor vascularization. Compared to the large vascular changes induced by ADT, RT induced minor vascular changes. Correlating DCE MRI and qIHC parameters unveiled the semi-quantitative parameters area under curve (AUC) from initial time-points to strongly correlate with VD and VF, whereas estimation of vessel size (VS) by DCE MRI required pharmacokinetic modeling. HF was not correlated to any DCE MRI parameter, however, AHS may be estimated after pharmacokinetic modeling. Interestingly, such

  20. 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

  1. 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.

  2. Efficacy of walking exercise in promoting cognitive-psychosocial functions in men with prostate cancer receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    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

  3. 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

  4. 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.

  5. Androgen receptor regulated microRNA miR-182-5p promotes prostate cancer progression by targeting the ARRDC3/ITGB4 pathway.

    Science.gov (United States)

    Yao, Jingjing; Xu, Chen; Fang, Ziyu; Li, Yaoming; Liu, Houqi; Wang, Yue; Xu, Chuanliang; Sun, Yinghao

    2016-05-20

    MicroRNAs (miRNAs) are important endogenous gene regulators that play key roles in prostate cancer development and metastasis. However, specific miRNA expression patterns in prostate cancer tissues from Chinese patients remain largely unknown. In this study, we compared miRNA expression patterns in 65 pairs of prostate cancer and para-cancer tissues by RNA sequencing and found that miR-182-5p was the most up-regulated miRNA in prostate cancer tissues. The result was validated using realtime PCR in 18 pairs of prostate cancer and para-cancer tissues. In in vitro analysis, it was confirmed that miR-182-5p promotes prostate cancer cell proliferation, invasion and migration and inhibit apoptosis. In addition, the androgen receptor directly regulated the transcription of miR-182-5p, which could target to the 3'UTR of ARRDC3 mRNA and affect the expression of ARRDC3 and its downstream gene ITGB4. For the in vivo experiment, miR-182-5p overexpression also promoted the growth and progression of prostate cancer tumors. In this regard, we suggest that miR-182-5p may be a key androgen receptor-regulated factor that contributes to the development and metastasis of Chinese prostate cancers and may be a potential target for the early diagnosis and therapeutic studies of prostate cancer. PMID:27109471

  6. First pharmacophore-based identification of androgen receptor down-regulating agents: discovery of potent anti-prostate cancer agents.

    Science.gov (United States)

    Purushottamachar, Puranik; Khandelwal, Aakanksha; Chopra, Pankaj; Maheshwari, Neha; Gediya, Lalji K; Vasaitis, Tadas S; Bruno, Robert D; Clement, Omoshile O; Njar, Vincent C O

    2007-05-15

    A qualitative 3D pharmacophore model (a common feature based model or Catalyst HipHop algorithm) was developed for well-known natural product androgen receptor down-regulating agents (ARDAs). The four common chemical features identified included: one hydrophobic group, one ring aromatic group, and two hydrogen bond acceptors. This model served as a template in virtual screening of the Maybridge and NCI databases that resulted in identification of six new ARDAs (EC(50) values 17.5-212 microM). Five of these molecules strongly inhibited the growth of human prostate LNCaP cells. These novel compounds may be used as leads to develop other novel anti-prostate cancer agents. PMID:17383188

  7. 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.

  8. 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

    OpenAIRE

    Thorsen, Lene; Nilsen, Tormod S; Raastad, Truls; Courneya, Kerry S.; Skovlund, Eva; Fosså, Sophie D

    2012-01-01

    Background 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 design...

  9. 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

    OpenAIRE

    Thorsen Lene; Nilsen Tormod S; Raastad Truls; Courneya Kerry S; Skovlund Eva; Fosså Sophie D

    2012-01-01

    Abstract Background 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 dete...

  10. 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

    OpenAIRE

    Thorsen, Lene; Nilsen, Tormod Skogstad; Raastad, Truls; Courneya, Kerry S.; Skovlund, Eva; Fosså, Sophie Dorothea

    2012-01-01

    Background 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...

  11. A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy

    OpenAIRE

    Haseen Farhana; Murray Liam J; O'Neill Roisin F; O'Sullivan Joe M; Cantwell Marie M

    2010-01-01

    Abstract Background Treatment with Androgen Deprivation Therapy (ADT) for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer surviv...

  12. The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) in prostate cancer patients undergoing androgen deprivation therapy: study protocol for a randomized controlled trial

    OpenAIRE

    Focht, Brian C; Lucas, Alexander R.; Grainger, Elizabeth; Simpson, Christina; Thomas-Ahner, Jennifer M.; Clinton, Steven K

    2014-01-01

    Background Androgen deprivation therapy (ADT) is the foundation of treatment for men with metastatic prostate cancer and is now frequently incorporated into multimodality strategies for the curative treatment of locally advanced prostate cancer. Nevertheless, the catabolic effects of ADT result in meaningful adverse effects on physiological and quality of life outcomes, which may, in turn, increase the risk of functional decline, frailty, cardiovascular disease, and metabolic syndrome. Recent...

  13. 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

  14. Can prophylactic breast irradiation contribute to cardiac toxicity in patients with prostate cancer receiving androgen suppressing drugs?

    International Nuclear Information System (INIS)

    Androgen suppression treatment (AST) might increase the risk of cardiac morbidity in prostate cancer patients. Possible explanations were provided, however, they disregard the potential contribution of prophylactic radiotherapy to the mamillary regions (PMRT, prescribed to avoid gynecomastia). We studied the exposure of the heart in a typical electron beam PMRT setting by evaluating computed tomography (CT) scans in 40 non-cancer patients (age 65 and 75 years in 50% each) and 17 prostate cancer patients. Five of the younger, 7 of the older and 4 of the cancer patients had significant cardiac disease. The median distance between skin and outer heart contour decreased with age. In all three groups, patients with cardiac morbidity had smaller distances. When using the CT-determined PMRT beam energy, 10% of the younger, 15% of the older and none of the prostate cancer patients would receive approximately 50% of the prescription dose to a part of the heart (2 had no history of cardiac disease). When using the clinically rather than CT-determined beam energy, as often done in daily practice, an additional 12.5% of the non-cancer and 12% of the prostate cancer patients would be exposed to comparably high doses. The present data provide preliminary evidence that PMRT might be a factor that contributes to cardiac side effects. Previous studies that established a relationship between AST and cardiac morbidity did not include information on delivery of PMRT

  15. 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

  16. Can we avoid high levels of dose escalation for high-risk prostate cancer in the setting of androgen deprivation?

    Science.gov (United States)

    Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

    2016-01-01

    Aim Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve outcomes in patients with high-risk prostate cancer. However, there is little evidence specifically evaluating DE-EBRT for patients with high-risk prostate cancer receiving ADT, particularly for EBRT doses >74 Gy. We aimed to determine whether DE-EBRT >74 Gy improves outcomes for patients with high-risk prostate cancer receiving long-term ADT. Patients and methods Patients with high-risk prostate cancer were treated on an institutional protocol prescribing 3–6 months neoadjuvant ADT and DE-EBRT, followed by 2 years of adjuvant ADT. Between 2006 and 2012, EBRT doses were escalated from 74 Gy to 76 Gy and then to 78 Gy. We interrogated our electronic medical record to identify these patients and analyzed our results by comparing dose levels. Results In all, 479 patients were treated with a 68-month median follow-up. The 5-year biochemical disease-free survivals for the 74 Gy, 76 Gy, and 78 Gy groups were 87.8%, 86.9%, and 91.6%, respectively. The metastasis-free survivals were 95.5%, 94.5%, and 93.9%, respectively, and the prostate cancer-specific survivals were 100%, 94.4%, and 98.1%, respectively. Dose escalation had no impact on any outcome in either univariate or multivariate analysis. Conclusion There was no benefit of DE-EBRT >74 Gy in our cohort of high-risk prostate patients treated with long-term ADT. As dose escalation has higher risks of radiotherapy-induced toxicity, it may be feasible to omit dose escalation beyond 74 Gy in this group of patients. Randomized studies evaluating dose escalation for high-risk patients receiving ADT should be considered. PMID:27274277

  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. 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.

  19. 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

  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. 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

  2. [{sup 11}C]choline uptake with PET/CT for the initial diagnosis of prostate cancer: relation to PSA levels, tumour stage and anti-androgenic therapy

    Energy Technology Data Exchange (ETDEWEB)

    Giovacchini, Giampiero; Coradeschi, Elisa [University of Milano-Bicocca, Center for Molecular Bioimaging, Milan (Italy); Picchio, Maria; Bettinardi, Valentino [Scientific Institute San Raffaele, Department of Nuclear Medicine, Milan (Italy); Scattoni, Vincenzo [Scientific Institute San Raffaele, Department of Urology, Milan (Italy); Cozzarini, Cesare [Scientific Institute San Raffaele, Department of Radiation Oncology, Milan (Italy); Freschi, Massimo [Scientific Institute San Raffaele, Department of Pathology, Milan (Italy); Fazio, Ferruccio [University of Milano-Bicocca, Center for Molecular Bioimaging, Milan (Italy); Scientific Institute San Raffaele, Department of Nuclear Medicine, Milan (Italy); Scientific Institute San Raffaele, Department of Radiation Oncology, Milan (Italy); National Research Council, Institute for Bioimaging and Molecular Physiology, Milan (Italy); Messa, Cristina [University of Milano-Bicocca, Center for Molecular Bioimaging, Milan (Italy); National Research Council, Institute for Bioimaging and Molecular Physiology, Milan (Italy); University of Milano-Bicocca, Department Nuclear Medicine, San Gerardo Hospital, Monza (Italy)

    2008-06-15

    The accuracy of positron emission tomography (PET)/CT with [{sup 11}C]choline for the detection of prostate cancer is not well established. We assessed the dependence of [{sup 11}C]choline maximum standardized uptake values (SUV{sub max}) 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 [{sup 11}C]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 [{sup 11}C]choline SUV{sub max} 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 SUV{sub max} and PSA levels, Gleason score or pathological stage. On the contrary, a significant (P < 0.05) negative correlation was detected between SUV{sub max} and anti-androgenic therapy both in univariate (r {sup 2} = 0.24) and multivariate (r {sup 2} = 0.48) analyses. Prostate [{sup 11}C]choline uptake after bicalutamide therapy significantly (P < 0.05) decreased compared to baseline (6.4 {+-} 4.6 and 11.8 {+-} 5.3, respectively; group B). PET/CT with [{sup 11}C]choline is not suitable for the initial diagnosis and local staging of prostate cancer. PET/CT with [{sup 11}C]choline could be used to monitor the response to anti-androgenic therapy. (orig.)

  3. [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.)

  4. 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

  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. Survival Following Radiation and Androgen Suppression Therapy for Prostate Cancer in Healthy Older Men: Implications for Screening Recommendations

    International Nuclear Information System (INIS)

    Purpose: The U.S. Preventive Services Task Force has recommended against screening men over 75 for prostate cancer. We examined whether older healthy men could benefit from aggressive prostate cancer treatment. Methods and Materials: 206 men with intermediate to high risk localized prostate cancer randomized to 70 Gy of radiation (RT) or RT plus 6 months of androgen suppression therapy (RT+AST) constituted the study cohort. Within subgroups stratified by Adult Comorbidity Evaluation-27 comorbidity score and age, Cox multivariable analysis was used to determine whether treatment with RT+AST as compared with RT was associated with a decreased risk of death. Results: Among healthy men (i.e., with mild or no comorbidity), 78 were older than the median age of 72.4 years, and in this subgroup, RT+AST was associated with a significantly lower risk of death on multivariable analysis (adjusted hazard ratio = 0.36 (95% CI=0.13-0.98), p = 0.046, with significantly lower 8-year mortality estimates of 16.5% vs. 41.4% (p = 0.011). Conversely, among men with moderate or severe comorbidity, 24 were older than the median age of 73, and in this subgroup, treatment with RT+AST was associated with a higher risk of death (adjusted hazard ratio = 5.2 (1.3-20.2), p = 0.018). Conclusion: In older men with mild or no comorbidity, treatment with RT+AST was associated with improved survival compared with treatment with RT alone, suggesting that healthy older men may derive the same benefits from prostate cancer treatment as younger men. We therefore suggest that prostate cancer screening recommendations should not be based on strict age cutoffs alone but should also take into account comorbidity.

  7. Prostate cancer in African-American men: outcome following radiation therapy with or without adjuvant androgen ablation

    International Nuclear Information System (INIS)

    Purpose: To compare the outcome of irradiated clinically localized prostate cancer in African-American and white patients. Methods and Materials: This was a retrospective review of 1,201 men, 116 African-American and 1,085 white, with T1-T3, N0/NX, M0 prostate cancer receiving external radiation between 1987 and 1996. Pretreatment characteristics, treatment parameters, and outcome (relapse or rising prostate-specific antigen [PSA] levels, local recurrence, metastatic relapse, and survival) were compared between the groups using univariate and multivariate statistical methods. Results: There were no significant differences between African-American and white patients in T-stage, Gleason score, prostatic acid phosphatase (PAP) level, and testosterone level. African-Americans had a significantly lower incidence of abnormal digital rectal findings and a proportionally higher incidence of obstructive urinary symptoms at presentation and tended to be somewhat younger. A major difference between the two groups was in the significantly higher PSA levels among African-Americans (median, 14 ng/ml) than among white patients (median, 9.5 ng/ml). This translated into a higher incidence of unfavorable disease according to our criteria (39% vs. 25%) among African-Americans and, thus, to the more frequent use of adjuvant androgen ablation and to somewhat higher radiation doses in these patients. With a median follow-up of 42 months the overall 6-year freedom from relapse for African-Americans was 63% compared to 61% for whites (p = 0.634). We found no significant differences in biochemical relapse rates between any subgroups of African-Americans and whites. Specifically, even patients who did not have androgen ablation, when stratified by PSA levels, had similar outcomes regardless of race. Likewise, local recurrence and metastasis rates were not significantly different between the two groups. Conclusions: Although African-American patients tend to have higher pretreatment PSA

  8. Re: Final Report of the Intergroup Randomized Study of Combined AndrogenDeprivation Therapy Plus Radiotherapy Versus Androgen-Deprivation Therapy Alone in Locally Advanced Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Malcolm D. Mason

    2015-06-01

    Full Text Available No certain treatment recommendations were given for locally advanced or high-risk prostate cancer in the European Association of Urology (EAU guidelines (1. In the guidelines, studies supporting surgery or radiotherapy (RT were listed, and the readers were left alone to make their own decisions. In the present study, Mason et al. reported the impact of adding RT to androgen deprivation therapy (ADT. One thousand two hundred and five patients with T3- 4, N0/Nx, M0 prostate cancer or T1-2 disease with either PSA more than 40 μg/L or PSA 20 to 40 μg/L plus Gleason score of 8 to 10 were randomized to ADT alone (n=602 or to ADT+RT (n=603. A lower dose radiation 64 to 69 Gy was used for RT. Overall survival (OS risk reduction was 30% for ADT+RT group (P<0.001 at a median follow-up of 8 years. Cancer-specific survival (CSS was significantly improved by the addition of RT to ADT (HR: 0.46, 95% CI: 0.34 to 0.61; p<0.001. Patients on ADT+RT reported a higher frequency of adverse events related to bowel toxicity. However, reported frequency of ADT-related toxicities (impotence, hot flushes, urinary frequency, ischemia, and hypertension were similar for both arms. The present study provided results of high-risk patients in a longer median follow-up time than SPCG-7 study (2. Because the study took place between 1995 and 2005, less than 70 Gy was used for RT. Even at lower radiation doses, the authors confirmed that adding RT to ADT improved both OS and cancer-specific survival (CSS with minimal general toxicity. In the modern era, improved RT techniques may help achieve better outcomes with much higher radiation doses without increased morbidity in this group of patients

  9. 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

  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

    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.

  13. 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)

  14. 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

  15. 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

  16. 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

  17. 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.

  18. Long-term androgen deprivation increases Grade 2 and higher late morbidity in prostate cancer patients treated with three-dimensional conformal radiation therapy

    International Nuclear Information System (INIS)

    Purpose: To determine whether the use of androgen deprivation (AD) increases late morbidity when combined with high-dose three-dimensional conformal radiation therapy (3D-CRT). Methods and materials: Between May 1989 and November 1998, 1,204 patients were treated for prostate cancer with 3D-CRT to a median dose of 74 Gy. Patients were evaluated every 3-6 months. No AD was given to 945 patients, whereas 140 and 119 patients, respectively, received short-term AD (STAD; ≤6 months) and long-term AD (LTAD; > 6 months). Radiation morbidity was graded according to the Fox Chase modification of the Late Effects Normal Tissue Task Force late morbidity scale. Covariates in the multivariate analysis (MVA) included age, history of diabetes mellitus, prostate-specific antigen (PSA) level, Gleason score, T category, RT field size, total RT dose, use of rectal shielding, and AD status (no AD vs. STAD vs. LTAD). Results: The only independent predictor for Grade 2 or higher genitourinary (GU) morbidity in the MVA was the use of AD (p = 0.0065). The 5-year risk of Grade 2 or higher GU morbidity was 8% for no AD, 8% for STAD, and 14% for LTAD (p = 0.02). Independent predictors of Grade 2 or higher gastrointestinal (GI) morbidity in the MVA were the use of AD (p = 0.0079), higher total radiation dose (p < 0.0001), the lack of a rectal shield (p = 0.0003), and older age (p = 0.0009). The 5-year actuarial risk of Grade 2 or higher GI morbidity was 17% for no AD vs. 18% for STAD and 26% for LTAD (p = 0.017). Conclusions: The use of LTAD seems to significantly increase the risk of both GU and GI morbidity for patients treated with 3D-CRT

  19. 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.

  20. 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.)

  1. 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)

    Chakraborty, Sandipan; Kumar, Avinash; Butt, Nasir A; Zhang, Liangfen; Williams, Raquema; Rimando, Agnes M; Biswas, Pradip K; Levenson, Anait S

    2016-04-26

    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 conventional anti-androgenic agents. Resveratrol and its natural analogs exhibit varying degrees of anti-androgenic effects on tumor growth suppression in prostate cancer. However, the structural basis for the observed differential activity remains unknown. Here, anti-androgenic activities of resveratrol and its natural analogs, namely, pterostilbene, piceatannol and trimethoxy-resveratrol were studied in LNCaP cells expressing T877A mutant AR and atomistic simulations were employed to establish the structure activity relationship. Interestingly, essential hydrogen bonding contacts and the binding energies of resveratrol analogs with AR ligand binding domain (LBD), emerge as key differentiating factors for varying anti-androgenic action. Among all the analogs, pterostilbene exhibited strongest anti-androgenic activity and its binding energy and hydrogen bonding interactions pattern closely resembled pure anti-androgen, flutamide. Principal component analysis of our simulation studies revealed that androgenic compounds bind more strongly to AR LBD compared to anti-androgenic compounds and provide conformational stabilization of the receptor in essential subspace. The present study provides critical insight into the structure-activity relationship of the anti-androgenic action of resveratrol analogs, which can be translated further to design novel highly potent anti-androgenic stilbenes. PMID:27063447

  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. 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.

  4. Characterization of 2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine at androgen receptor: mechanistic support for its role in prostate cancer.

    Science.gov (United States)

    Glass-Holmes, Mashunté; Aguilar, Byron J; Gragg, Richard D; Darling-Reed, Selina; Goodman, Carl B

    2015-01-01

    2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP) is a dietary mutagenic carcinogen that has been shown not only to induce the formation of DNA adducts, but is capable of inducing tumors in the colon, mammary, and prostate glands. The normal development and maturation of the prostate gland, as well as early progression of prostate cancer, is dependent on androgens acting on the androgen receptor (AR). The actual mechanism by which PhIP interacts with our biological system and its potential interaction at the AR has yet to be fully defined. Here, we describe our work in evaluating the molecular events associated with PhIP-mediated disruption of AR function in LNCaP human prostate cancer cells. We demonstrate, by molecular docking simulation, that PhIP and its metabolite can bind to the ligand-binding domain (LBD). The binding competes with dihydrotestosterone (DHT) in the native AR binding cavity of the receptor. In vitro assays show that PhIP increase AR protein expression in LNCaP cells and alters its responsiveness through PSA protein and mRNA expression. We propose that the mechanism for the tissue-specific carcinogenicity seen in the rat prostate tumors and the presumptive human prostate cancer associated with the consumption of well-done meat may be mediated by this receptor activation. Our results indicate that PhIP may play an important role in modifications of AR function. PMID:25628930

  5. Hinokitiol, a metal chelator derived from natural plants, suppresses cell growth and disrupts androgen receptor signaling in prostate carcinoma cell lines

    International Nuclear Information System (INIS)

    Hinokitiol (β-thujaplicin), a troplone-related compound found in the heartwood of cupressaceous plants, strongly inhibits the proliferation of a broad range of tumor cell lines. This is the first report to demonstrate that hinokitiol, a metal chelator derived from natural plants, suppresses cell growth and disrupts AR signaling in prostate carcinoma cell lines. Our present studies indicate that hinokitiol suppresses androgen/AR-mediated cell growth and androgen-stimulated DNA synthesis by [3H]thymidine incorporation in a dose- and time-dependent manner. Hinokitiol simultaneously suppresses the intracellular and secreted PSA levels, a marker for the progression of prostate cancer. Hinokitiol significantly represses the AR mRNA and protein expression in a dose- and time-dependent manner. Additionally, the ligand-binding assay shows that hinokitiol blocks binding of the synthetic androgen [3H]R1881 to AR in LNCaP cells. These findings collectively suggest that hinokitiol is potentially effective against prostate cancer in vitro, and thus it might become a novel chemopreventive or chemotherapeutic agent for prostate cancer

  6. (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.

  7. [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.

  8. 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.

  9. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

    International Nuclear Information System (INIS)

    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. 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. 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 laminin-binding integrins, nor can they be linked to

  10. Met-Independent Hepatocyte Growth Factor-mediated regulation of cell adhesion in human prostate cancer cells

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    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

  11. 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

  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. Docetaxel induces Bcl-2- and pro-apoptotic caspase-independent death of human prostate cancer DU145 cells.

    Science.gov (United States)

    Ogura, Takeharu; Tanaka, Yoshiyuki; Tamaki, Hiroki; Harada, Mamoru

    2016-06-01

    Docetaxel is a useful chemotherapeutic agent for the first-line treatment of hormone-refractory prostate cancer. Abnormal expression of Bcl-2 is commonly found in cancer cells, which increases their anti-apoptotic potency and chemoresistance. We investigated the effects of Bcl-2 expression status on the susceptibility of DU145 cells, an androgen-independent human prostate cancer cell line, to docetaxel and other anticancer agents. A panel of Bcl-2-expressing DU145 cell lines was established. Bcl-2 expression levels were unrelated to the susceptibility of DU145 cells to docetaxel. The sensitivity of DU145 cells to cisplatin fluctuated, and the sensitivity to tumor necrosis factor (TNF)-α was decreased by Bcl-2 overexpression. In a xenograft mouse model, overexpression of Bcl-2 drastically decreased the sensitivity of DU145 cells to cisplatin and TNF-α; however, there was no change in the response to docetaxel. Fluorescent microscopy revealed that Bcl-2-overexpression had no effect on the docetaxel-induced death of DU145 cells, but significantly decreased DU145 cell death induced by cisplatin or TNF-α. Interestingly, docetaxel hardly induced caspase-3/7 activation in control or Bcl-2-overexpressing DU145 cells, but did at a low level in LNCaP cells, another prostate cancer cell line. Moreover, in contrast to LNCaP cells, the reduced viabilities of docetaxel-treated control and Bcl-2-overexpressing DU145 cells were not restored by the addition of either a Bid inhibitor or a panel of pro-apoptotic caspase inhibitors. These findings indicate that the antitumor effects of docetaxel on DU145 cells are independent of both Bcl-2 and pro-apoptotic caspases. PMID:27082738

  15. 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

  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. Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival.

    Directory of Open Access Journals (Sweden)

    Emma Hörnberg

    Full Text Available BACKGROUND: Constitutively active androgen receptor variants (AR-V lacking the ligand binding domain (LBD may promote the development of castration-resistant prostate cancer (CRPC. The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival. METHODOLOGY/PRINCIPAL FINDINGS: Hormone-naïve (n = 10 and CRPC bone metastases samples (n = 30 were obtained from 40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival. CONCLUSIONS/SIGNIFICANCE: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis.

  18. 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.

  19. Diabetes protects from prostate cancer by downregulating androgen receptor: new insights from LNCaP cells and PAC120 mouse model.

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    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.

  20. 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

  1. 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

    Directory of Open Access Journals (Sweden)

    Thorsen Lene

    2012-03-01

    Full Text Available Abstract Background 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. Methods/design 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

  2. 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

  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. 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.

  5. 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.

  6. 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

  7. 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...

  8. 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...

  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. 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.

  12. 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 ...

  13. 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

  14. 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

  15. 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

  16. 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.

  17. Mechanism and Function of Angiogenin in Prostate Cancer

    Science.gov (United States)

    Vanli, Nil; Guo-Fu, HU

    2016-01-01

    Angiogenin (ANG), the fifth member of the vertebrate-specific ribonuclease (RNase) A superfamily, is a secreted angiogenic ribonuclease strongly up-regulated in human prostate cancers. ANG is translocated to the nucleus in both prostate cancer epithelial cells and endothelial cells to exert its role in prostate cancer progression by mediating tumor angiogenesis, cancer cell survival and proliferation through rRNA biogenesis. ANG-stimulated rRNA is required not only for prostate intraepithelial neoplasia (PIN) formation, but also for androgen-independent growth of prostate cancer cells. Targeting ANG by various antagonists that inhibit its nuclear translocation, function and/or activity has proven to inhibit prostate cancer growth in animal models. Furthermore, the role of ANG in androgen independence has been firmly established, suggesting a strong rationale for therapeutically targeting ANG in the treatment of castration resistant prostate cancer. PMID:27175049

  18. 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.

  19. 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.

  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. Survival benefit of early androgen receptor inhibitor therapy in locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Thomsen, Frederik B; Brasso, Klaus; Christensen, Ib J;

    2015-01-01

    BACKGROUND: The optimal timing of endocrine therapy in non-metastatic prostate cancer (PCa) is still an issue of debate. METHODS: A randomised, double-blind, parallel-group trial comparing bicalutamide 150mg once daily with placebo in addition to standard care in patients with hormone-naïve, non-...

  2. Incorporating Androgen Deprivation With Dose-Escalated External-Beam Radiotherapy for Prostate Cancer.

    Science.gov (United States)

    Dosoretz, Arie P; Yu, James B

    2016-05-20

    The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.A 71-year-old man was seen by his primary care physician for routine evaluation in early 2015. On digital rectal examination, his prostate was moderately enlarged, although he had no obvious areas of palpable disease. His prostate-specific antigen (PSA) level was 7.1 ng/mL. A standard ultrasound-guided biopsy of his prostate revealed a 60-mL prostate volume and a single core (out of 12) of Gleason 3 + 3 disease. He chose to undergo surveillance. Six months later, his PSA level had risen to 10.0 ng/mL; there was still no palpable disease on digital rectal examination. Multiparametric magnetic resonance imaging of his prostate and pelvis revealed two suspicious intraprostatic lesions with restricted diffusion, focal and earlier enhancement with contrast than adjacent normal prostate, and hypointense features on T2-weighted imaging; these findings were highly suspicious for high-grade prostate cancer (Fig 1). Magnetic resonance imaging-ultrasound fusion targeted biopsy of each lesion yielded a total of four positive biopsy cores of Gleason 4 + 3 = 7, involving 50% to 80% of each core, with perineural invasion noted. The patient's medical history is notable for overweight (but not morbidly obese), hypercholesterolemia, hypertension, cataract surgeries, and inguinal hernia repair, but the patient is otherwise healthy. He has decided against prostatectomy and brachytherapy because of strong personal preference. In particular, he wanted to avoid anesthesia, and

  3. Systematic structure modifications of multitarget prostate cancer drug candidate galeterone to produce novel androgen receptor down-regulating agents as an approach to treatment of advanced prostate cancer.

    Science.gov (United States)

    Purushottamachar, Puranik; Godbole, Abhijit M; Gediya, Lalji K; Martin, Marlena S; Vasaitis, Tadas S; Kwegyir-Afful, Andrew K; Ramalingam, Senthilmurugan; Ates-Alagoz, Zeynep; Njar, Vincent C O

    2013-06-27

    As part of our program to explore the influence of small structural modifications of our drug candidate 3β-(hydroxy)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (galeterone, 5) on the modulation of the androgen receptor (AR), we have prepared and evaluated a series of novel C-3, C-16, and C-17 analogues. Using structure activity analysis, we established that the benzimidazole moiety at C-17 is essential and optimal and also that hydrophilic and heteroaromatic groups at C-3 enhance both antiproliferative (AP) and AR degrading (ARD) activities. The most potent antiproliferative compounds were 3β-(1H-imidazole-1-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (47), 3-((EZ)-hydroximino)-17-(1H-benzimidazol-1-yl)androsta-4,16-diene (36), and 3β-(pyridine-4-carboxylate)-17-(1H-benzimidazol-1-yl)androsta-5,16-diene (43), with GI50 values of 0.87, 1.91, and 2.57 μM, respectively. Compared to 5, compound 47 was 4- and 8-fold more potent with respect to AP and ARD activities, respectively. Importantly, we also discovered that our compounds, including 5, 36, 43, and 47, could degrade both full-length and truncated ARs in CWR22rv1 human prostate cancer cells. With these activities, they have potential for development as new drugs for the treatment of all forms of prostate cancer. PMID:23713567

  4. 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.

  5. 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.)

  6. 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.)

  7. 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.

  8. Expanded risk groups help determine which prostate radiotherapy sub-group may benefit from adjuvant androgen deprivation therapy

    International Nuclear Information System (INIS)

    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). 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. 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). 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

  9. 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.

  10. 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

  11. 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.

  12. Androgen depletion induces senescence in prostate cancer cells through down-regulation of Skp2

    Czech Academy of Sciences Publication Activity Database

    Pernicová, Zuzana; Slabáková, Eva; Kharaishvili, G.; Bouchal, J.; Král, M.; Kunická, Z.; Machala, M.; Kozubík, Alois; Souček, Karel

    2011-01-01

    Roč. 13, č. 6 (2011), s. 526-536. ISSN 1522-8002 R&D Projects: GA ČR(CZ) GA310/07/0961; GA MZd NS9600; GA MZd NS9956 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : prostate cancer * senescence * Skp2 Subject RIV: BO - Biophysics Impact factor: 5.946, year: 2011

  13. 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...

  14. 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

  15. 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.

  16. Long-term effects of developmental exposure to di-n-butyl-phthalate (DBP) on rat prostate: Proliferative and inflammatory disorders and a possible role of androgens

    International Nuclear Information System (INIS)

    In the present study we evaluated the toxic effects on the male adult rat prostate of DBP exposure during fetal and lactational periods, because although many studies have addressed the influence of phthalates on the male reproductive system, only a few have discussed their possible effects on prostate development. Pregnant females were distributed into two experimental groups: Control (C) and Treated (T). The females of the T group received DBP (100 mg/kg, by gavage) from gestation day 12 to postnatal day 21, while C rats received the vehicle (corn oil). In adulthood (90 days old), the animals were euthanized. The serum and testicular testosterone levels were measured. Ventral prostate was removed and weighed. Distal segment fragments of the ventral prostate were fixed and processed for histochemistry and immunohistochemistry to detect androgen receptor (AR) and Ki67 antigens. Protein extraction from ventral prostate fragments was performed for AR immunoblotting and Gelatin zymography for MMP-2 and MMP-9 (MMP, metalloproteinase). Stereological and histopathological analyses were also performed. Serum and testicular testosterone levels and prostate weight were comparable between groups. In the T group the relative proportions (%) of epithelial (C = 32.86; T = 42.04*) and stromal (C = 21.61; T = 27.88*) compartments were increased, while the luminal compartment was decreased (C = 45.54; T = 30.08*), *p < 0.05. In T, disseminated inflammatory infiltrate in the stroma, associated or not with epithelial dysplasia and PIN (Prostatic Intraepithelial Neoplasia), was observed. Increases in AR expression, proliferation index and metalloproteinase 9 (MMP-9) activity were noted in T animals. In some T animals, collagen fibrils accumulated adjacent to the epithelium. As far as we are aware, this is the first report in the literature showing that phthalates could play a role in proliferative and inflammatory disorders of the rat prostate.

  17. Total Androgen Blockade Versus a Luteinizing Hormone-Releasing Hormone Agonist Alone in Men With High-Risk Prostate Cancer Treated With Radiotherapy

    International Nuclear Information System (INIS)

    Purpose: To assess whether short-course total androgen blockade vs. a luteinizing hormone-releasing hormone (LHRH) agonist alone affects the risk of prostate cancer-specific mortality (PCSM) in men with localized but high-risk disease treated with radiotherapy. Methods and Materials: The study cohort comprised 628 men with T1-T4, N0, M0 prostate cancer with high-risk disease (prostate-specific antigen level >20 ng/mL, Gleason score ≥8, or clinical category ≥T3) treated with 45 Gy of external beam radiotherapy followed by a brachytherapy boost in addition to receiving a median of 4.3 (interquartile range [IQR], 3.6-6.4) months of hormonal blockade with an LHRH agonist plus an antiandrogen or monotherapy with an LHRH agonist. Fine and Gray's multivariable regression analysis was used to determine whether combination androgen suppression therapy (AST) vs. monotherapy affected the risk of PCSM, adjusting for treatment year, duration of AST, age, and known prognostic factors. Results: After a median follow-up of 4.9 (IQR, 3.5-6.5) years, men receiving combination AST had a lower risk of PCSM than those treated with monotherapy (adjusted hazard ratio [AHR], 0.18; 95% confidence interval [CI], 0.04-0.90; p = 0.04). An increasing prostate-specific antigen level (AHR, 2.70; 95% CI, 1.64-4.45; p < 0.001) and clinical category T3/4 disease (AHR, 29.6; 95% CI, 2.88-303.5; p = 0.004) were also associated with an increased risk of PCSM. Conclusions: In men with localized but high-risk prostate cancer treated with external beam radiotherapy and brachytherapy, short-course AST with an LHRH agonist plus an antiandrogen is associated with a decreased risk of PCSM when compared with monotherapy with an LHRH agonist.

  18. PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

    International Nuclear Information System (INIS)

    PCA3 is a non-coding RNA (ncRNA) that is highly expressed in prostate cancer (PCa) cells, but its functional role is unknown. To investigate its putative function in PCa biology, we used gene expression knockdown by small interference RNA, and also analyzed its involvement in androgen receptor (AR) signaling. LNCaP and PC3 cells were used as in vitro models for these functional assays, and three different siRNA sequences were specifically designed to target PCA3 exon 4. Transfected cells were analyzed by real-time qRT-PCR and cell growth, viability, and apoptosis assays. Associations between PCA3 and the androgen-receptor (AR) signaling pathway were investigated by treating LNCaP cells with 100 nM dihydrotestosterone (DHT) and with its antagonist (flutamide), and analyzing the expression of some AR-modulated genes (TMPRSS2, NDRG1, GREB1, PSA, AR, FGF8, CdK1, CdK2 and PMEPA1). PCA3 expression levels were investigated in different cell compartments by using differential centrifugation and qRT-PCR. LNCaP siPCA3-transfected cells significantly inhibited cell growth and viability, and increased the proportion of cells in the sub G0/G1 phase of the cell cycle and the percentage of pyknotic nuclei, compared to those transfected with scramble siRNA (siSCr)-transfected cells. DHT-treated LNCaP cells induced a significant upregulation of PCA3 expression, which was reversed by flutamide. In siPCA3/LNCaP-transfected cells, the expression of AR target genes was downregulated compared to siSCr-transfected cells. The siPCA3 transfection also counteracted DHT stimulatory effects on the AR signaling cascade, significantly downregulating expression of the AR target gene. Analysis of PCA3 expression in different cell compartments provided evidence that the main functional roles of PCA3 occur in the nuclei and microsomal cell fractions. Our findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival, in part through modulating AR signaling, which may raise new

  19. PCA3 noncoding RNA is involved in the control of prostate-cancer cell survival and modulates androgen receptor signaling

    Directory of Open Access Journals (Sweden)

    Ferreira Luciana Bueno

    2012-11-01

    Full Text Available Abstract Background PCA3 is a non-coding RNA (ncRNA that is highly expressed in prostate cancer (PCa cells, but its functional role is unknown. To investigate its putative function in PCa biology, we used gene expression knockdown by small interference RNA, and also analyzed its involvement in androgen receptor (AR signaling. Methods LNCaP and PC3 cells were used as in vitro models for these functional assays, and three different siRNA sequences were specifically designed to target PCA3 exon 4. Transfected cells were analyzed by real-time qRT-PCR and cell growth, viability, and apoptosis assays. Associations between PCA3 and the androgen-receptor (AR signaling pathway were investigated by treating LNCaP cells with 100 nM dihydrotestosterone (DHT and with its antagonist (flutamide, and analyzing the expression of some AR-modulated genes (TMPRSS2, NDRG1, GREB1, PSA, AR, FGF8, CdK1, CdK2 and PMEPA1. PCA3 expression levels were investigated in different cell compartments by using differential centrifugation and qRT-PCR. Results LNCaP siPCA3-transfected cells significantly inhibited cell growth and viability, and increased the proportion of cells in the sub G0/G1 phase of the cell cycle and the percentage of pyknotic nuclei, compared to those transfected with scramble siRNA (siSCr-transfected cells. DHT-treated LNCaP cells induced a significant upregulation of PCA3 expression, which was reversed by flutamide. In siPCA3/LNCaP-transfected cells, the expression of AR target genes was downregulated compared to siSCr-transfected cells. The siPCA3 transfection also counteracted DHT stimulatory effects on the AR signaling cascade, significantly downregulating expression of the AR target gene. Analysis of PCA3 expression in different cell compartments provided evidence that the main functional roles of PCA3 occur in the nuclei and microsomal cell fractions. Conclusions Our findings suggest that the ncRNA PCA3 is involved in the control of PCa cell survival

  20. 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

  1. 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...

  2. Androgen Receptor Inactivation Contributes to Antitumor Efficacy of CYP17 Inhibitor VN/124-1 in Prostate Cancer

    Science.gov (United States)

    Vasaitis, Tadas; Belosay, Aashvini; Schayowitz, Adam; Khandelwal, Aakanksha; Chopra, Pankaj; Gediya, Lalji K.; Guo, Zhiyong; Fang, Hong-Bin; Njar, Vincent C. O.; Brodie, Angela M. H.

    2008-01-01

    We previously reported that our novel compound 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (VN/124-1) is a potent CYP17 inhibitor/antiandrogen and strongly inhibits the formation and proliferation of human prostate cancer LAPC4 tumor xenografts in SCID mice. In this study, we report that VN/124-1 and other novel CYP17 inhibitors also cause down-regulation of AR protein expression in vitro and in vivo. This mechanism of action appears to contribute to their antitumor efficacy. We compared the in vivo antitumor efficacy of VN/124-1 with that of castration and a clinically used antiandrogen, casodex, and show that VN/124-1 is more potent than castration in LAPC4 xenograft model. Treatment with VN/124-1 (0.13 mmol/kg/twice daily) was also very effective in preventing the formation of LAPC4 tumors (6.94 vs. 2410.28 mm3 in control group). VN/124-1 (0.13 mmol/kg/twice daily) and VN/124-1 (0.13 mmol/kg/twice daily) + castration induced regression of LAPC4 tumor xenografts by 26.55% and 60.67%, respectively. Treatments with casodex (0.13 mmol/kg/twice daily) or castration caused significant tumor suppression compared with control. Furthermore, treatment with VN/124-1 caused marked down-regulation of AR protein expression, in contrast to treatments with casodex or castration that caused significant up-regulation of AR protein expression. The results suggest that VN/124-1 acts by several mechanisms (CPY17 inhibition, competitive inhibition and down-regulation of the androgen receptor). These actions contribute to inhibition of the formation of LAPC4 tumors and cause regression of growth of established tumors. VN/124-1 is more efficacious than castration in the LAPC4 xenograft model suggesting the compound has potential for the treatment of prostate cancer. PMID:18723482

  3. 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.

  4. 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

  5. 前列腺癌细胞中两个雄激素应答元件调节雄激素对MMP-2表达的调控%Dual androgen-response elements mediate androgen regulation of MMP-2 expression in prostate cancer cells

    Institute of Scientific and Technical Information of China (English)

    B.Y.Li; X.B.Liao; A.Fujito; J.B.Thrasher; F.Y.Shen; P.Y.Xu

    2007-01-01

    Aim:To characterize the matrix metalloproteinases (MMP)-2 promoter and to identify androgen response elements (AREs) involved in androgen-induced MMP-2 expression. Methods: MMP-2 mRNA levels was determined by reverse transcription-polymerase chain reaction (RT-PCR). MMP-2 promoter-driven luciferase assays were used to determine the fragments responsible for androgen-induced activity. Chromatin-immunoprecipitation assay and electrophoretic mobility shift assays (EMSA) were used to verify the identified AREs in the MMP-2 promoter. Results: Androgen significantly induced MMP-2 expression at the mRNA level, which was blocked by the androgen antagonist bicalutamide. Deletion of a region encompassing base pairs -1 591 to -1259 (relative to the start codon) of the MMP-2 promoter led to a significant loss of androgen-induced reporter activity. Additional deletion of the 5'-region up to -562 bp further reduced the androgen-induced MMP-2 promoter activity. Sequence analysis of these two regions revealed two putative ARE motifs. Introducing mutations in the putative ARE motifs by site-directed mutagenesis approach resulted in a dramatic loss of androgen-induced MMP-2 promoter activity, indicating that the putative ARE motifs are required for androgen-stimulated MMP-2 expression. Most importantly, the androgen receptor (AR) interacted with both motif-containing promoter regions in vivo in a chromatin immunoprecipitation assay after androgen treatment.Furthermore, the AR specifically bound to the wild-type but not mutated ARE motifs-containing probes in an in vitro EMSA assay. Conclusion: Two ARE motifs were identified to be responsible for androgen-induced MMP-2 expression in prostate cancer cells.

  6. 17beta-estradiol-induced activation of ERK1/2 through endogenous androgen receptor-estradiol receptor alpha-Src complex in human prostate cells.

    Science.gov (United States)

    Chieffi, Paolo; Kisslinger, Annamaria; Sinisi, Antonio A; Abbondanza, Ciro; Tramontano, Donatella

    2003-09-01

    We examined the effect of estrogens on mitogen-activated protein kinase (MAPK) in EPN cells, a line of epithelial cells derived from human normal prostate. 17beta-estradiol (E2) caused a rapid and transient activation of MAPK (ERK1/2) within 5 min. This effect was counteracted by the anti-estrogen ICI 182-780 and by MEK inhibitor PD098059. The activation of ERK1/2 through 17beta-estradiol triggered simultaneous association of endogenous androgen receptor, estrogen receptor alpha and Src. In addition, E2 stimulated the proliferation of EPN cells, suggesting that the formation of the ternary complex and the consequent activation of ERKs are implicated in the mechanism regulating proliferation of epithelial prostate cells. PMID:12888920

  7. Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

    Directory of Open Access Journals (Sweden)

    Shakespeare TP

    2016-03-01

    Full Text Available Thomas P Shakespeare,1,2 Shea W Wilcox,1 Noel J Aherne1,2 1Department of Radiation Oncology, North Coast Cancer Institute, 2Faculty of Medicine, Rural Clinical School, The University of New South Wales, Coffs Harbour, New South Wales, Australia Background: Both dose-escalated external beam radiotherapy (DE-EBRT and androgen deprivation therapy (ADT improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings: In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion: There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. Keywords: radiotherapy, IMRT, dose, dose escalation, dose de-escalation, androgen deprivation therapy

  8. Berberine inhibits androgen synthesis by interaction with aldo-keto reductase 1C3 in 22Rv1 prostate cancer cells.

    Science.gov (United States)

    Tian, Yuantong; Zhao, Lijing; Wang, Ye; Zhang, Haitao; Xu, Duo; Zhao, Xuejian; Li, Yi; Li, Jing

    2016-01-01

    Aldo-keto reductase family 1 member C3 has recently been regarded as a potential therapeutic target in castrate-resistant prostate cancer. Herein, we investigated whether berberine delayed the progression of castrate-resistant prostate cancer by reducing androgen synthesis through the inhibition of Aldo-keto reductase family 1 member C3. Cell viability and cellular testosterone content were measured in prostate cancer cells. Aldo-keto reductase family 1 member C3 mRNA and protein level were detected by RT-PCR and Western bolt analyses, respectively. Computer analysis with AutoDock Tools explored the molecular interaction of berberine with Aldo-keto reductase family 1 member C3. We found that berberine inhibited 22Rv1 cells proliferation and decreased cellular testosterone formation in a dose-dependent manner. Berberine inhibited Aldo-keto reductase family 1 member C3 enzyme activity, rather than influenced mRNA and protein expressions. Molecular docking study demonstrated that berberine could enter the active center of Aldo-keto reductase family 1 member C3 and form p-p interaction with the amino-acid residue Phe306 and Phe311. In conclusion, the structural interaction of berberine with Aldo-keto reductase family 1 member C3 is attributed to the suppression of Aldo-keto reductase family 1 member C3 enzyme activity and the inhibition of 22Rv1 prostate cancer cell growth by decreasing the intracellular androgen synthesis. Our result provides the experimental basis for the design, research, and development of AKR1C3 inhibitors using berberine as the lead compound. PMID:26698234

  9. Pyridine analogues of curcumin exhibit high activity for inhibiting CWR-22Rv1 human prostate cancer cell growth and androgen receptor activation

    Science.gov (United States)

    ZHOU, DAI-YING; ZHAO, SU-QING; DU, ZHI-YUN; ZHENG, XI; ZHANG, KUN

    2016-01-01

    The concentrations required for curcumin to exert its anticancer activity (IC50, 20 µM) are difficult to achieve in the blood plasma of patients, due to the low bioavailability of the compound. Therefore, much effort has been devoted to the development of curcumin analogues that exhibit stronger anticancer activity and a lower IC50 than curcumin. The present study investigated twelve pyridine analogues of curcumin, labeled as groups AN, BN, EN and FN, to determine their effects in CWR-22Rv1 human prostate cancer cells. The inhibitory effects of these compounds on testosterone (TT)-induced androgen receptor (AR) activity was determined by performing an AR-linked luciferase assay and by TT-induced expression of prostate-specific antigen. The results of the current study suggested that the FN group of analogues had the strongest inhibitory effect of growth on CWR-22Rv1 cultured cells, and were the most potent inhibitor of AR activity compared with curcumin, and the AN, BN and EN analogues. Thus, the results of the present study indicate the inhibition of the AR pathways as a potential mechanism for the anticancer effect of curcumin analogues in human prostate cancer cells. Furthermore, curcumin analogues with pyridine as a distal ring and tetrahydrothiopyran-4-one as a linker may be good candidates for the development of novel drugs for the treatment of prostate cancer, by targeting the AR signaling pathway. PMID:27313760

  10. A randomised controlled trial to evaluate the efficacy of a 6 month dietary and physical activity intervention for prostate cancer patients receiving androgen deprivation therapy

    Directory of Open Access Journals (Sweden)

    Haseen Farhana

    2010-08-01

    Full Text Available Abstract Background Treatment with Androgen Deprivation Therapy (ADT for prostate cancer is associated with changes in body composition including increased fat and decreased lean mass; increased fatigue, and a reduction in quality of life. No study to date has evaluated the effect of dietary and physical activity modification on the side-effects related to ADT. The aim of this study is to evaluate the efficacy of a 6-month dietary and physical activity intervention for prostate cancer survivors receiving ADT to minimise the changes in body composition, fatigue and quality of life, typically associated with ADT. Methods Men are recruited to this study if their treatment plan is to receive ADT for at least 6 months. Men who are randomised to the intervention arm receive a home-based tailored intervention to meet the following guidelines a ≥ 5 servings vegetables and fruits/day; b 30%-35% of total energy from fat, and Discussion The results of this study will provide detailed information on diet and physical activity levels in prostate cancer patients treated with ADT and will test the feasibility and efficacy of a diet and physical activity intervention which could provide essential information to develop guidelines for prostate cancer patients to minimise the side effects related to ADT. Trial registration ISRCTN trial number ISCRTN75282423

  11. Comparison of animal models for the evaluation of radiolabeled androgens

    International Nuclear Information System (INIS)

    Biodistribution of two 18F-labeled androgens and an 124I/125I-labeled androgen were studied in five androgen receptor (prostate) animal models with or lacking sex hormone binding globulin (SHBG). As models for androgen-receptor positive ovarian cancer, xenografts of three human ovarian cancer cell lines were tested in SCID mice. SHBG in the prostate model systems significantly affects the metabolism, clearance, and distribution of the radiolabeled androgens in several tissues, but ovarian cancer animal models were disappointing

  12. No increased risk of coronary heart disease for patients receiving androgen deprivation therapy for prostate cancer in Chinese/Taiwanese men.

    Science.gov (United States)

    Wang, L H; Liu, C K; Chen, C H; Kao, L T; Lin, H C; Huang, C Y

    2016-01-01

    The relationship between androgen deprivation therapy (ADT) and coronary heart disease (CHD) remains controversial. Furthermore, the majority of such studies focused on Caucasian populations, and there is still a paucity of studies among Asian populations. This population-based study aimed to investigate the relationship between ADT and CHD in an ethnic Chinese (i.e., Taiwanese) population. We used data sourced from the Taiwan 'Longitudinal Health Insurance Database'. This study included 1278 patients with prostate cancer in the study group and 1278 subjects without prostate cancer in the comparison group. Each patient was individually tracked for a 3-year period to identify those who had subsequently received a diagnosis of CHD. The results showed that the incidence rate of CHD during the 3-year follow-up period was 4.69 (95% CI: 2.99-5.48) per 100 person-years and 2.67 (95% CI: 2.15-3.27) per 100 person-years for the study and comparison cohort, respectively. The Cox proportional hazard regression showed that the hazard ratio for CHD during the 3-year follow-up period for prostate cancer patients was 1.65 (95% confidence interval (CI) = 1.25-2.16) compared with comparison subjects after adjusting for patients' geographic location, monthly income, urbanization level, hypertension, diabetes, hyperlipidemia, and stroke. However, we failed to find a significant difference in the adjusted hazard of CHD during the 3-year follow-up period between prostate cancer patients who did and those who did not receive ADT (hazard ratio = 1.12, 95% CI = 0.79-1.59). We concluded that prostate cancer but not ADT was significantly associated with CHD. In addition, a common cause of prostate cancer and coronary heart disease could exist. PMID:26711703

  13. Can we avoid dose escalation for intermediate-risk prostate cancer in the setting of short-course neoadjuvant androgen deprivation?

    Science.gov (United States)

    Shakespeare, Thomas P; Wilcox, Shea W; Aherne, Noel J

    2016-01-01

    Background Both dose-escalated external beam radiotherapy (DE-EBRT) and androgen deprivation therapy (ADT) improve the outcomes in patients with intermediate-risk prostate cancer. Despite this, there are only few reports evaluating DE-EBRT for patients with intermediate-risk prostate cancer receiving neoadjuvant ADT, and virtually no studies investigating dose escalation >74 Gy in this setting. We aimed to determine whether DE-EBRT >74 Gy improved the outcomes for patients with intermediate-risk prostate cancer who received neoadjuvant ADT. Findings In our institution, patients with intermediate-risk prostate cancer were treated with neoadjuvant ADT and DE-EBRT, with doses sequentially increasing from 74 Gy to 76 Gy and then to 78 Gy between 2006 and 2012. We identified 435 patients treated with DE-EBRT and ADT, with a median follow-up of 70 months. For the 74 Gy, 76 Gy, and 78 Gy groups, five-year biochemical disease-free survival rates were 95.0%, 97.8%, and 95.3%, respectively; metastasis-free survival rates were 99.1%, 100.0%, and 98.6%, respectively; and prostate cancer-specific survival rate was 100% for all three dose levels. There was no significant benefit for dose escalation either on univariate or multivariate analysis for any outcome. Conclusion There was no benefit for DE-EBRT >74 Gy in our cohort of intermediate-risk prostate cancer patients treated with neoadjuvant ADT. Given the higher risks of toxicity associated with dose escalation, it may be feasible to omit dose escalation in this group of patients. Randomized studies evaluating dose de-escalation should be considered. PMID:27073327

  14. Effects of recreational soccer in men with prostate cancer undergoing androgen deprivation therapy: study protocol for the ‘FC Prostate’ randomized controlled trial

    International Nuclear Information System (INIS)

    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 (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. Using a single-center randomized controlled design, 80 men with histologically confirmed locally advanced or disseminated prostate cancer undergoing ADT for 6 months or more at The Copenhagen University Hospital will be enrolled on this trial. After baseline assessments eligible participants will be randomly assigned to a soccer training group or a control group receiving usual care. The soccer intervention will consist of 12 weeks of training 2–3 times/week for 45–60 min after which the assessment protocol will be repeated. Soccer training will then continue bi-weekly for an additional 20 weeks at the end of which all measures will be repeated to allow for additional analyses of long-term effects. The primary endpoint is changes in lean body mass from baseline to 12 weeks assessed by dual X-ray absorptiometry scan. Secondary endpoints include changes of cardiovascular, metabolic, and physical function parameters, as well as markers of bone metabolism and patient-reported outcomes. The FC Prostate trial will assess the safety and efficacy of a novel soccer-training approach to cancer rehabilitation on a number of clinically important health outcomes in men with advanced prostate cancer during ADT. The results may pave the way for innovative, community-based interventions in the approach to treating prostate cancer. ClinicalTrials.gov: http

  15. ASC-J9(®) suppresses castration resistant prostate cancer progression via degrading the enzalutamide-induced androgen receptor mutant AR-F876L.

    Science.gov (United States)

    Wang, Ronghao; Lin, Wanying; Lin, Changyi; Li, Lei; Sun, Yin; Chang, Chawnshang

    2016-08-28

    Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance. Here, we demonstrate that the AR degradation enhancer, ASC-J9(®), not only degrades wild-type AR, but also has the ability to target AR-F876L. The consequence of suppressing AR-F876L may then abrogate AR-F876L mediated CRPC cell proliferation and metastasis. Thus, developing ASC-J9(®) as a new therapeutic approach may represent a novel therapy to better suppress CRPC that has already developed Enz resistance. PMID:27233475

  16. Androgen deprivation therapy influences the uptake of 11C-choline in patients with recurrent prostate cancer: the preliminary results of a sequential PET/CT study

    International Nuclear Information System (INIS)

    The influence of androgen deprivation therapy (ADT) on 11C-choline uptake in patients with prostate cancer (PC) has not yet been clarified. The aim of our study was to investigate this issue by means of sequential 11C-choline positron emission tomography (PET)/CT in patients with recurrent PC. We retrospectively studied 14 recurrent PC patients (mean age 67 years, range 55-82) during follow-up after radical prostatectomy (RP) with rising serum prostate-specific antigen (PSA) levels. All patients had undergone at least two consecutive 11C-choline PET/CT scans: the first 11C-choline PET/CT before commencing ADT and the second 11C-choline PET/CT after 6 months of ADT administration. The mean serum PSA level before ADT was 17.0 ± 44.1 ng/ml. After 6 months of ADT administration the PSA value significantly decreased in comparison to baseline (PSA = 2.4 ± 3.1 ng/ml, p 11C-choline PET/CT for metastatic spread, while after 6 months of ADT administration in 9 of 14 patients 11C-choline PET/CT became negative. These preliminary results suggest that ADT significantly reduces 11C-choline uptake in androgen-sensitive PC patients. (orig.)

  17. Development and Implementation of a High-Throughput High-Content Screening Assay to Identify Inhibitors of Androgen Receptor Nuclear Localization in Castration-Resistant Prostate Cancer Cells.

    Science.gov (United States)

    Johnston, Paul A; Nguyen, Minh M; Dar, Javid A; Ai, Junkui; Wang, Yujuan; Masoodi, Khalid Z; Shun, Tongying; Shinde, Sunita; Camarco, Daniel P; Hua, Yun; Huryn, Donna M; Wilson, Gabriela Mustata; Lazo, John S; Nelson, Joel B; Wipf, Peter; Wang, Zhou

    2016-05-01

    Patients with castration-resistant prostate cancer (CRPC) can be treated with abiraterone, a potent inhibitor of androgen synthesis, or enzalutamide, a second-generation androgen receptor (AR) antagonist, both targeting AR signaling. However, most patients relapse after several months of therapy and a majority of patients with relapsed CRPC tumors express the AR target gene prostate-specific antigen (PSA), suggesting that AR signaling is reactivated and can be targeted again to inhibit the relapsed tumors. Novel small molecules capable of inhibiting AR function may lead to urgently needed therapies for patients resistant to abiraterone, enzalutamide, and/or other previously approved antiandrogen therapies. Here, we describe a high-throughput high-content screening (HCS) campaign to identify small-molecule inhibitors of AR nuclear localization in the C4-2 CRPC cell line stably transfected with GFP-AR-GFP (2GFP-AR). The implementation of this HCS assay to screen a National Institutes of Health library of 219,055 compounds led to the discovery of 3 small molecules capable of inhibiting AR nuclear localization and function in C4-2 cells, demonstrating the feasibility of using this cell-based phenotypic assay to identify small molecules targeting the subcellular localization of AR. Furthermore, the three hit compounds provide opportunities to develop novel AR drugs with potential for therapeutic intervention in CRPC patients who have relapsed after treatment with antiandrogens, such as abiraterone and/or enzalutamide. PMID:27187604

  18. Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk non-metastatic prostate cancer: a systematic review and meta-analysis

    International Nuclear Information System (INIS)

    Objectives: to investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent. Materials and Methods: A systematic search was performed in electronic databases. Data from randomized trials comparing different durations of hormone blockade was collected for pooled analysis. Overall survival, disease-free survival, disease-specific survival and toxicity were the outcomes of interest. Meta-analyses were performed using random-effects model. Results: Six studies met the eligibility criteria. For overall survival, the pooled data from the studies demonstrated a statistically significant benefit for longer hormone deprivation (Hazard Ratio 0.84; 95% CI 0.74 - 0.96). A statistically significant benefit was also found for disease-free survival (Hazard Ratio 0.74; 95% CI 0.62 - 0.89), and disease-specific survival (Hazard Ratio 0.73; 95% CI 0.62 - 0.85). Studies with longer blockade duration arm demonstrated greater benefit. Toxicity was low, with no increase in cardiovascular events. Conclusions: Longer duration of androgen deprivation combined to radiotherapy prolongs OS, DFS and DSS in patients with intermediate and high-risk non-metastatic prostate cancer. However, this evidence is based on trials using older radiation techniques, and further research of combination of androgen deprivation and new RT technologies may be warranted. (author)

  19. Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk non-metastatic prostate cancer: a systematic review and meta-analysis

    Energy Technology Data Exchange (ETDEWEB)

    Leal, Frederico; Figueiredo, Maximiliano Augusto Novis de; Sasse, Andre Deeke, E-mail: sasse@cevon.com.br [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2015-05-15

    Objectives: to investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent. Materials and Methods: A systematic search was performed in electronic databases. Data from randomized trials comparing different durations of hormone blockade was collected for pooled analysis. Overall survival, disease-free survival, disease-specific survival and toxicity were the outcomes of interest. Meta-analyses were performed using random-effects model. Results: Six studies met the eligibility criteria. For overall survival, the pooled data from the studies demonstrated a statistically significant benefit for longer hormone deprivation (Hazard Ratio 0.84; 95% CI 0.74 - 0.96). A statistically significant benefit was also found for disease-free survival (Hazard Ratio 0.74; 95% CI 0.62 - 0.89), and disease-specific survival (Hazard Ratio 0.73; 95% CI 0.62 - 0.85). Studies with longer blockade duration arm demonstrated greater benefit. Toxicity was low, with no increase in cardiovascular events. Conclusions: Longer duration of androgen deprivation combined to radiotherapy prolongs OS, DFS and DSS in patients with intermediate and high-risk non-metastatic prostate cancer. However, this evidence is based on trials using older radiation techniques, and further research of combination of androgen deprivation and new RT technologies may be warranted. (author)

  20. 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...

  1. In vivo modulation of androgen receptor by androgens

    Institute of Scientific and Technical Information of China (English)

    V·L·Kumar; V·Kumar

    2002-01-01

    Aim:To study the effect of androgen and antiandrogen on the level of androgen receptor(AR)mRNA.Methods:The totalRNA was extracted from the prostate and analyzed by slot blot analysis,The blots were hybrid-ized with ARcDNA probe and 1Aprobe(internal control)and autoradionraphy was performed.The intensity of signal was measured with a densitometer and the ratio of AR RNAand1ARNAwas calculated.Results:Androgenic deprivation produced by castration decreased the weight of the prostate and increased the levels of ARmRNA.Treatment of the castrated rats with testostrone increased the weight of prostate and decreased the levels of ARmRNA.Treatment of normal rats with flutamide decreased the weight of the gland and increased the levels of AR mRNA.Conclusion:Androgens produce proliferative effect on the prostate and negatively regulate the AR transcription.

  2. Partial association of restriction polymorphism of the ligand binding domain of human androgen receptor in prostate cancer

    Directory of Open Access Journals (Sweden)

    Mohamed Hessien

    2016-04-01

    Conclusion: Our results indicate that the loss of the restriction integrity in the C-terminal part (exons: 7 and 8 of the LBD is associated with the progression of benign prostatic hyperplasia to prostate cancer.

  3. Prostate cancer stem cells: The case for model systems

    Directory of Open Access Journals (Sweden)

    Paul G Hynes

    2012-01-01

    Full Text Available Advanced prostate cancers are treated with androgen deprivation therapy, which usually leads to a rapid and significant reduction in tumor burden but subsequent development of castration-resistant and metastatic disease almost always occurs. The source of tumor heterogeneity and the accompanying mechanisms leading to treatment resistance are major areas of prostate cancer research. Although our understanding of tumor heterogeneity is evolving, the functional isolation of tumor propagating populations, also known as cancer stem cells (CSCs, is fundamental to the identification and molecular characterization of castration-resistant prostate cancer cells. Of clinical importance, knowledge of prostate CSCs has implications for design of next generation-targeted therapies aimed at both eradicating primary tumor mass and preventing castration-resistant disease. The inability to routinely transplant fractionated primary human prostate tumors has prevented progress in analyzing the source of heterogeneous and treatment-resistant populations in prostate cancer. Here, we briefly overview the mechanisms of castration resistance, including the hypothesis for the existence of androgen-independent prostate CSCs. Finally, we discuss the interpretation of preclinical models and their utility for characterizing prostate CSCs in androgen-replete and androgen-deprived conditions.

  4. 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....../or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified on...... ERG-status. Risk reclassification and time-dependent area under the ROC curves were used to assess the discriminative ability of ERG-status. Time to PSA-nadir, proportion achieving PSA-nadir ≤0.2 ng/ml, and risk of PCa-specific death were secondary endpoints. RESULTS: Median follow-up was 6.8 years...

  5. Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome.

    Science.gov (United States)

    Foster, Christopher S; Falconer, Alison; Dodson, Andrew R; Norman, Andrew R; Dennis, Nening; Fletcher, Anne; Southgate, Christine; Dowe, Anna; Dearnaley, David; Jhavar, Sameer; Eeles, Rosalind; Feber, Andrew; Cooper, Colin S

    2004-08-01

    E2F transcription factors, including E2F3, directly modulate expression of EZH2. Recently, overexpression of the EZH2 gene has been implicated in the development of human prostate cancer. In tissue microrarray studies we now show that expression of high levels of nuclear E2F3 occurs in a high proportion (98/147, 67%) of human prostate cancers, but is a rare event in non-neoplastic prostatic epithelium suggesting a role for E2F3 overexpression in prostate carcinogenesis. Patients with prostate cancer exhibiting immunohistochemically detectable nuclear E2F3 expression have poorer overall survival (P=0.0022) and cause-specific survival (P=0.0047) than patients without detectable E2F3 expression. When patients are stratified according to the maximum percentage of E2F3-positive nuclei identified within their prostate cancers (up to 20, 21-40%, etc.), there is an increasingly significant association between E2F3 staining and risk of death both for overall survival (P=0.0014) and for cause-specific survival (P=0.0004). Multivariate analyses select E2F3 expression as an independent factor predicting overall survival (unstratified P=0.0103, stratified P=0.0086) and cause-specific survival (unstratified P=0.0288, stratified P=0.0072). When these results are considered together with published data on EZH2 and on the E2F3 control protein pRB, we conclude that the pRB-E2F3-EZH2 control axis may have a critical role in modulating aggressiveness of individual human prostate cancer. PMID:15184867

  6. External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer

    International Nuclear Information System (INIS)

    Purpose: To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. Materials and Methods: From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. Results: Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, there was no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. Conclusions: There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine-125 provide similar bDFS, DMFS, and OS. (author)

  7. External beam radiation therapy and a low-dose-rate brachytherapy boost without or with androgen deprivation therapy for prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Strom, Tobin J.; Hutchinson, Sean Z.; Shrinath, Kushagra; Cruz, Alex A.; Figura, Nicholas B.; Nethers, Kevin; Biagioli, Matthew C.; Fernandez, Daniel C.; Heysek, Randy V.; Wilder, Richard B., E-mail: richard.wilder@moffitt.org [Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL (United States)

    2014-07-15

    Purpose: To assess outcomes with external beam radiation therapy (EBRT) and a low-dose-rate (LDR) brachytherapy boost without or with androgen deprivation therapy (ADT) for prostate cancer. Materials and Methods: From January 2001 through August 2011, 120 intermediate-risk or high-risk prostate cancer patients were treated with EBRT to a total dose of 4,500 cGy in 25 daily fractions and a palladium-103 LDR brachytherapy boost of 10,000 cGy (n = 90) or an iodine-125 LDR brachytherapy boost of 11,000 cGy (n = 30). ADT, consisting of a gonadotropin-releasing hormone agonist ± an anti-androgen, was administered to 29/92 (32%) intermediate-risk patients for a median duration of 4 months and 26/28 (93%) high-risk patients for a median duration of 28 months. Results: Median follow-up was 5.2 years (range, 1.1-12.8 years). There was no statistically-significant difference in biochemical disease-free survival (bDFS), distant metastasis-free survival (DMFS), or overall survival (OS) without or with ADT. Also, there was no statistically-significant difference in bDFS, DMFS, or OS with a palladium-103 vs. an iodine-125 LDR brachytherapy boost. Conclusions: There was no statistically-significant difference in outcomes with the addition of ADT, though the power of the current study was limited. The Radiation Therapy Oncology Group 0815 and 0924 phase III trials, which have accrual targets of more than 1,500 men, will help to clarify the role ADT in locally-advanced prostate cancer patients treated with EBRT and a brachytherapy boost. Palladium-103 and iodine-125 provide similar bDFS, DMFS, and OS. (author)

  8. A mutation in the ligand binding domain of the androgen receptor of human LNCaP cells affects steroid binding characteristics and response to anti-androgens

    NARCIS (Netherlands)

    J. Veldscholte (Jos); C. Ris-Stalpers (Carolyn); G.G.J.M. Kuiper (George); G.W. Jenster (Guido); C.A. Berrevoets (Cor); H.J.H.M. Claassen (Eric); H.C.J. van Rooij (Henri); J. Trapman (Jan); A.O. Brinkmann (Albert); E. Mulder (Eppo)

    1990-01-01

    markdownabstractAbstract INCaP prostate tumor cells contain an abnormal androgen receptor system. Progestagens, estradiol and anti-androgens can compete with androgens for binding to the androgen receptor and can stimulate both cell growth and excretion of prostate specific acid phosphatase. We ha

  9. Three linked nomograms for predicting biochemical failure in prostate cancer treated with radiotherapy plus androgen deprivation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lopez-Torrecilla, Jose [Hospital General Universitario, Servicio Oncologia Radioterapica- ERESA, Valencia (Spain); Boladeras, Anna [Institut Catala d' Oncologia, S.Oncologia Radioterapica, Hospitalet (Spain); Angeles Cabeza, Maria [Hospital Universitario Doce de Octubre, S.Oncologia Radioterapica, Madrid (Spain); Zapatero, Almudena [Hospital Universitario de la Princesa, S.Oncologia Radioterapica, Madrid (Spain); Jove, Josep [Institut Catala d' Oncologia, S.Oncologia Radioterapica, Badalona (Spain); Esteban, Luis M. [Universidad de Zaragoza, Escuela Universitaria Politecnica de La Almunia, Zaragoza (Spain); Henriquez, Ivan [Hospital Universitari Sant Joan de Reus, S.Oncologia Radioterapica, Reus (Spain); Casana, Manuel; Mengual, Jose Luis [Fundacion Instituto Valenciano de Oncologia, S.Oncologia Radioterapica, Valencia (Spain); Gonzalez-San Segundo, Carmen [Hospital Universitario Gregorio Maranon, S.Oncologia Radioterapica, Madrid (Spain); Gomez-Caamano, Antonio [Hospital Clinico Universitario de Santiago, S.Oncologia Radioterapica, Santiago de Compostela (Spain); Hervas, Asuncion [Hospital Universitario Ramon y Cajal, S.Oncologia Radioterapica, Madrid (Spain); Munoz, Julia Luisa [Hospital Infanta Cristina, S.Oncologia Radioterapica, Badajoz (Spain); Sanz, Gerardo [Universidad de Zaragoza, Departamento de Metodos Estadisticos, Zaragoza (Spain)

    2015-10-15

    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.) [German] Es wurden Nomogramme etabliert, um ein biochemisches Rezidiv (BCR) nach einer Strahlentherapie (RT) vorhersagen zu koennen und den Einfluss der charakteristischen Variablen der RT und der Androgendeprivationstherapie (ADT) dabei moeglichst gering zu halten. Unser Ziel ist es, ein neues stratifiziertes Instrument

  10. Hormone therapy for prostate cancer

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/patientinstructions/000908.htm Hormone therapy for prostate cancer To use the sharing ... helps slow the growth of prostate cancer. Male Hormones and Prostate Cancer Androgens are male sex hormones. ...

  11. Combination External Beam Radiation and Brachytherapy Boost With Androgen Suppression for Treatment of Intermediate-Risk Prostate Cancer: An Initial Report of CALGB 99809

    International Nuclear Information System (INIS)

    Purpose: Transperineal prostate brachytherapy (TPPB) can be used with external beam radiation therapy (EBRT) to provide a high-dose conformal boost to the prostate. The results of a multicenter Phase II trial assessing safety of combination of EBRT and TPPB boost with androgen suppression (AST) in treatment of intermediate-risk prostate cancer are present here. Materials and Methods: Patients had intermediate-risk prostate cancer. Six months of AST was administered. EBRT to the prostate and seminal vesicles was administered to 45Gy followed by TPPB using either 125I or 103Pd to deliver an additional 100Gy or 90Gy. Toxicity was graded using the National Cancer Institute CTC version 2 and the Radiation Therapy Oncology Group late radiation morbidity scoring systems. Results: Sixty-three patients were enrolled. Median follow-up was 38 months. Side effects of AST including sexual dysfunction and vasomotor symptoms were commonly observed. Apart from erectile dysfunction, short-term Grade 2 and 3 toxicity was noted in 21% and 7%, primarily genitourinary related. Long-term Grade 2 and 3 toxicities were noted in 13% and 3%. Two patients had Grade 3 dysuria that resolved with longer follow-up. The most common Grade 2 long-term toxicity was urinary frequency (5%). No biochemical or clinical evidence of progression was noted for the entire cohort. Conclusions: In a cooperative group setting, combination EBRT and TPPB boost with 6 months of AST was generally well tolerated with expected genitourinary and gastrointestinal toxicities. Further follow-up will be required to fully assess long-term toxicity and cancer control

  12. Androgen Deprivation Therapy Does Not Impact Cause-Specific or Overall Survival in High-Risk Prostate Cancer Managed With Brachytherapy and Supplemental External Beam

    International Nuclear Information System (INIS)

    Purpose: To determine cause-specific survival (CSS), biochemical progression-free survival (bPFS), and overall survival (OS) in high-risk prostate cancer patients undergoing brachytherapy with or without supplemental therapies. Methods and Materials: Between April 1995 and July 2002, 204 patients with high-risk prostate cancer (Gleason score ≥8 or prostate-specific antigen [PSA] >20 ng/mL or clinical stage ≥T2c) underwent brachytherapy. Median follow-up was 7.0 years. The bPFS was defined by a PSA ≤0.40 ng/mL after nadir. Multiple clinical, treatment, and dosimetric parameters were evaluated for the impact on survival. Results: The 10-year CSS, bPFS, and OS were 88.9%, 86.6%, and 68.6%, respectively. A statistically significant difference in bPFS was discerned between hormone naive, ADT ≤6 months, and ADT >6 month cohorts (79.7% vs. 95.% vs. 89.9%, p = 0.032). Androgen deprivation therapy (ADT) did not impact CSS or OS. For bPFS patients, the median posttreatment PSA was <0.04 ng/mL. A Cox linear regression analysis demonstrated that Gleason score was the best predictor of CSS, whereas percent positive biopsies and duration of ADT best predicted for bPFS. The OS was best predicted by Gleason score and diabetes. Thirty-eight patients have died, with 26 of the deaths from cardiovascular/pulmonary disease or second malignancy. Eleven patients have died of metastatic prostate cancer. Conclusions: The ADT improved 10-year bPFS without statistical impact on CSS or OS. Death as a result of cardiovascular/pulmonary disease and second malignancies were more than twice as common as prostate cancer deaths. Strategies to improve cardiovascular health should positively impact OS

  13. Molecular mechanisms of androgen receptor functions

    NARCIS (Netherlands)

    K. Steketee (Karine)

    2007-01-01

    textabstractThe androgens testosterone (T) and dihydrotestosterone (DHT) are steroid hormones, which are necessary for development and maintenance of the functions of the male sex organs, including the prostate. Androgens also play an important role in benign abnormalities of the prostate and in the

  14. 前列腺癌雄激素剥夺治疗与骨质丢失%Androgen deprivation therapy for prostate cancer and bone loss

    Institute of Scientific and Technical Information of China (English)

    吴燕华; 刘伟

    2013-01-01

    Prostate cancer is one of the common malignant tumors of the urinary system in the male. The incidence of prostate cancer in China is rising rapidly. At present, the vast majority of patients are receiving androgen deprivation therapy (ADT). Compared with chemotherapy, ADT has less toxic side effect, and it is more likely to be accepted by patients. However, ADT causes a range of adverse reactions. This paper reviews the risk of bone loss after ADT and the prevention and treatment strategies in patients with prostate cancer.%目的 前列腺癌是男性泌尿系统常见的恶性肿瘤之一.我国前列腺癌的发病率在迅速上升.目前绝大多数患者采取雄激素剥夺治疗,与化疗相比,雄激素剥夺治疗的毒副作用较轻,更容易被患者接受,但仍会引起一系列的不良反应,本文将对前列腺癌雄激素剥夺治疗后骨质丢失的情况及防治策略进行综述.

  15. Survival benefit associated with adjuvant androgen deprivation therapy combined with radiotherapy for high- and low-risk patients with nonmetastatic prostate cancer

    International Nuclear Information System (INIS)

    Background: The use of adjuvant androgen deprivation therapy (ADT) combined with radiotherapy has become common in low-risk patients, although clinical trials have focused primarily on high-risk patients. This study examines the effectiveness of adjuvant ADT combined with radiotherapy for a wide range of patients treated in the 1990s. Methods and Materials: Prostate cancer survival was examined in a population based cohort of 31,643 patients aged 65 to 85 years who were diagnosed with nonmetastatic prostate cancer and treated with external beam radiotherapy and/or brachytherapy. Instrumental variable analysis methods were used to control for selection bias. Results: Patients with stage T3/T4 disease who received adjuvant ADT experienced improved 5-year and 8-year survival. No survival advantage was observed for men with T1/T2 disease during this interval. Conclusion: High-risk patients who receive primary radiotherapy have benefited from adjuvant ADT, whereas low-risk patients with disease confined to the prostate have not yet benefited from adjuvant therapy within the first 8 years after treatment. These findings are consistent with practice guidelines, which recommend adjuvant ADT for patients with high-risk disease

  16. Targeting intratumoral androgens: statins and beyond.

    Science.gov (United States)

    Schweizer, Michael T; Yu, Evan Y

    2016-09-01

    While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone-sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins). PMID:27583031

  17. Development of an immunotherapeutic adenovirus targeting hormone-independent prostate cancer

    Directory of Open Access Journals (Sweden)

    Kim JS

    2013-11-01

    Full Text Available Jae Sik Kim,1 Sang Don Lee,2 Sang Jin Lee,3 Moon Kee Chung21Department of Urology, The Catholic University of Korea Incheon St Mary's Hospital, Incheon, 2Pusan National University Yangsan Hospital and Research Institute for Convergence of Biomedical Science and Technology, Yangsan, 3Genitourinary Cancer Branch, National Cancer Center, Goyang, KoreaBackground: To develop a targeting therapy for hormone-independent prostate cancer, we constructed and characterized conditionally replicating oncolytic adenovirus (Ad equipped with mRFP(monomeric red fluorescence protein/ttk (modified herpes simplex virus thymidine kinase This construct was then further modified to express both mRFP/ttk and a soluble form of cytokine FLT3L (fms-related tyrosine kinase 3 ligand simultaneously.Methods: To construct the recombinant oncolytic adenovirus, E1a and E4 genes, which are necessary for adenovirus replication, were controlled by the prostate-specific enhancer sequence (PSES targeting prostate cancer cells expressing prostate-specific antigen (PSA and prostate-specific membrane antigen (PSMA. Simultaneously, it expressed the mRFP/ttk fusion protein in order to be able to elicit the cytotoxic effect.Results: The Ad5/35PSES.mRFP/ttk chimeric recombinant adenovirus was generated successfully. When replication of Ad5/35PSES.mRFP/ttk was evaluated in prostate cancer cell lines under fluorescence microscopy, red fluorescence intensity increased more in LNCaP cells, suggesting that the mRFP/ttk fusion protein was folded functionally. In addition, the replication assay including wild-type adenovirus as a positive control showed that PSES-positive cells (LNCaP and CWR22rv permitted virus replication but not PSES-negative cells (DU145 and PC3. Next, we evaluated the killing activity of this recombinant adenovirus. The Ad5/35PSES.mRFP/ttk killed LNCaP and CWR22rv more effectively. Unlike PSES-positive cells, DU145 and PC3 were resistant to killing by this recombinant

  18. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate

    International Nuclear Information System (INIS)

    Purpose: To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival. Methods and Materials: The study was conducted from 1987 to 1991. Eligible patients were those with bulky tumors (T2-T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II. Results: As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p 0.04), disease-free survival (33% vs. 21%, p=0.004), biochemical disease-free survival = PSA <1.5 (24% vs. 10%, p<0.0001), and cause-specific mortality (23% vs. 31%, p=0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score 2-6. In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p=0.015). In patients with Gleason 7-10 tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival. Conclusion: In patients with Gleason score 2-6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival

  19. Development of an immunotherapeutic adenovirus targeting hormone-independent prostate cancer

    OpenAIRE

    Kim JS; Lee SD; Lee SJ; Chung MK

    2013-01-01

    Jae Sik Kim,1 Sang Don Lee,2 Sang Jin Lee,3 Moon Kee Chung21Department of Urology, The Catholic University of Korea Incheon St Mary's Hospital, Incheon, 2Pusan National University Yangsan Hospital and Research Institute for Convergence of Biomedical Science and Technology, Yangsan, 3Genitourinary Cancer Branch, National Cancer Center, Goyang, KoreaBackground: To develop a targeting therapy for hormone-independent prostate cancer, we constructed and characterized conditionally replicating ...

  20. ANDROGEN REPRESSION OF CYTOKERATIN GENE EXPRESSION DURING RAT PROSTATE DIFFERENTIATION: EVIDENCE FOR ANEPITHELIAL STEM CELL-ASSOCIATED MARKER

    Institute of Scientific and Technical Information of China (English)

    王晓怀; Jer-TsongHsieh

    1994-01-01

    Cytokeratin(CK) 8 mRNA expression in developing and degenerating rat prostate was studied using in situhybridization with an antisense RNA-probe.It was found that:1) the CK 8 antisense probe was accumulated only within prostatic epithelial cells;2)after castration,CK 8mRNA signals in vetral prostate(VP) sections were significantly increased,and elevated CK 8 mRNA expression persisted even long after prostate involution was complete;and 3)during prostate development,the strongest CK 8 mRNA staining was found in the early neonatal prostatic epithelia which were composed mainly of prostatic stem cells.Thereafer,a shift of CK 8 mRNA staining to peripheral regions and decreased overall CK 8 mRNA levels were noted .These data indicate that excessive expression of CK-8 mRNA is a characteristic of prostatic stem cells,and CK molecules are excellent markers for determing the hierarchical pathway of cell differentiation in prostate epithelium.

  1. JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

    OpenAIRE

    Hübner, Anette; Mulholland, David J; Standen, Claire L.; Karasarides, Maria; Cavanagh-Kyros, Julie; Barrett, Tamera; Chi, Hongbo; Dale L Greiner; Tournier, Cathy; Sawyers, Charles L.; Richard A Flavell; Wu, Hong; Davis, Roger J

    2012-01-01

    The c-Jun NH2-terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (ΔJnk ΔPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (Δ...

  2. Fatigue and other adverse effects in men treated by pelvic radiation and long-term androgen deprivation for locally advanced prostate cancer.

    Science.gov (United States)

    Lilleby, Wolfgang; Stensvold, Andreas; Dahl, Alv A

    2016-07-01

    Background We compared the development of adverse effects and psychosocial measures from baseline to 36-month follow-up in patients with prostate cancer (T1-3 M0) referred to our department for definitive radiotherapy encompassing the prostate and pelvic lymph nodes (RAD + IMRT) or radiotherapy to the prostatic gland only (RAD), applied with standard adjuvant androgen deprivation (AD) in all patients. Few studies have explored the impact of fatigue on patients' reported quality of life (QoL) after combined therapy for prostate cancer. Material and methods The 206 consecutive eligible men (RAD + IMRT = 64 and RAD = 142) completed the UCLA-PCI questionnaire for adverse effects at baseline, 12, 24, and 36 months. QoL, anxiety and depression, and fatigue were rated at the same time points. Between-group and longitudinal within-group changes at different time points were reported. At 36 months variables associated with fatigue were analyzed with regression analyses. Results Our main novel finding is the long-term high level of fatigue and high prevalence of chronic fatigue, affecting patients receiving radiotherapy combined with long-term AD. Except for urinary bother in the RAD + IMRT group all functions and the other bothers mean scores were significantly worse at 36 months compared to baseline. In multivariable analyses only physical QoL remained significantly associated with fatigue at 36-months follow-up. Conclusions Fatigue and impaired QoL in patients considered to curative irradiation with long-term AD should be addressed when counseling men to combined treatment. PMID:26959297

  3. Effect of Whole Pelvic Radiotherapy for Patients With Locally Advanced Prostate Cancer Treated With Radiotherapy and Long-Term Androgen Deprivation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mantini, Giovanna [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Tagliaferri, Luca, E-mail: luca.tagliaferri@rm.unicatt.it [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Mattiucci, Gian Carlo; Balducci, Mario; Frascino, Vincenzo; Dinapoli, Nicola [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy); Di Gesu, Cinzia; Ippolito, Edy; Morganti, Alessio G. [Department of Radiotherapy, John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso (Italy); Cellini, Numa [Department of Radiotherapy, Policlinico Universitario A. Gemelli, Catholic University, Rome (Italy)

    2011-12-01

    Purpose: To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). Methods and materials: Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score {>=}7 and/or prostate-specific antigen level {>=}20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). Results: A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12-38). With a median follow-up of 52 months (range, 20-150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p = NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p = .03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p = NS). Conclusions: Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial.

  4. Effect of Whole Pelvic Radiotherapy for Patients With Locally Advanced Prostate Cancer Treated With Radiotherapy and Long-Term Androgen Deprivation Therapy

    International Nuclear Information System (INIS)

    Purpose: To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). Methods and materials: Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score ≥7 and/or prostate-specific antigen level ≥20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). Results: A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12–38). With a median follow-up of 52 months (range, 20–150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p = NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p = .03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p = NS). Conclusions: Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial.

  5. Cardiovascular Adaptations to Recreational Football Training in Men with Type 2 Diabetes, Untrained Elderly Men and in Men with Prostate Cancer Receiving Androgen Deprivation Therapy

    DEFF Research Database (Denmark)

    Schmidt, Jakob Friis

    Numerous people in the general population are not suffuciently physically active and the use of new exercise training modalities which could promote physically active lifestyles are important. The present PhD thesis includes studies , which investigated the effect of recreational football training...... in middle-aged men with type 2 diabetes, 65-75-year-old untrained men, men with prostate cancer receiving androgen deprivation therapy and the effect of life-long participation in football training in veteran football players. The primary purpose was to evaluate the structure and function of the...... heart by ultrasound (echocardiography) and in three studies football training was shown to have marked positive effects on the heart function. In addition cardiorespiratory fitness, blood pressure, resting heart rate and peripheral microvascular function was evaluated and in men with type 2 diabetes...

  6. Efficacy of recreational football on bone health, body composition, and physical functioning in men with prostate cancer undergoing androgen deprivation therapy

    DEFF Research Database (Denmark)

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

    2016-01-01

    Androgen deprivation therapy (ADT) for prostate cancer (PCa) impairs musculoskeletal health. We evaluated the efficacy of 32-week football training on bone mineral density (BMD) and physical functioning in men undergoing ADT for PCa. Football training improved the femoral shaft and total hip BMD...... and physical functioning parameters compared to control. INTRODUCTION: ADT is a mainstay in PCa management. Side effects include decreased bone and muscle strength and increased fracture rates. The purpose of the present study was to evaluate the effects of 32 weeks of football training on BMD, bone...... turnover markers (BTMs), body composition, and physical functioning in men with PCa undergoing ADT. METHODS: Men receiving ADT >6 months (n = 57) were randomly allocated to a football training group (FTG) (n = 29) practising 2-3 times per week for 45-60 min or to a standard care control group (CON) (n = 28...

  7. High-dose-rate interstitial brachytherapy in combination with androgen deprivation therapy for prostate cancer. Are high-risk patients good candidates

    International Nuclear Information System (INIS)

    To evaluate the effectiveness of high-dose-rate interstitial brachytherapy (HDR-ISBT) as the only form of radiotherapy for high-risk prostate cancer patients. Between July 2003 and June 2008, we retrospectively evaluated the outcomes of 48 high-risk patients who had undergone HDR-ISBT at the National Hospital Organization Osaka National Hospital. Risk group classification was according to the criteria described in the National Comprehensive Cancer Network (NCCN) guidelines. Median follow-up was 73 months (range 12-109 months). Neoadjuvant androgen deprivation therapy (ADT) was administered to all 48 patients; 12 patients also received adjuvant ADT. Maximal androgen blockade was performed in 37 patients. Median total treatment duration was 8 months (range 3-45 months). The planned prescribed dose was 54 Gy in 9 fractions over 5 days for the first 13 patients and 49 Gy in 7 fractions over 4 days for 34 patients. Only one patient who was over 80 years old received 38 Gy in 4 fractions over 3 days. The clinical target volume (CTV) was calculated for the prostate gland and the medial side of the seminal vesicles. A 10-mm cranial margin was added to the CTV to create the planning target volume (PTV). The 5-year overall survival and biochemical control rates were 98 and 87 %, respectively. Grade 3 late genitourinary and gastrointestinal complications occurred in 2 patients (4 %) and 1 patient (2 %), respectively; grade 2 late genitourinary and gastrointestinal complications occurred in 5 patients (10 %) and 1 patient (2 %), respectively. Even for high-risk patients, HDR-ISBT as the only form of radiotherapy combined with ADT achieved promising biochemical control results, with acceptable late genitourinary and gastrointestinal complication rates. (orig.)

  8. TLR3 engagement induces IRF-3-dependent apoptosis in androgen-sensitive prostate cancer cells and inhibits tumour growth in vivo.

    Science.gov (United States)

    Gambara, Guido; Desideri, Marianna; Stoppacciaro, Antonella; Padula, Fabrizio; De Cesaris, Paola; Starace, Donatella; Tubaro, Andrea; Del Bufalo, Donatella; Filippini, Antonio; Ziparo, Elio; Riccioli, Anna

    2015-02-01

    Toll-like receptors (TLRs) are a family of highly conserved transmembrane proteins expressed in epithelial and immune cells that recognize pathogen associated molecular patterns. Besides their role in immune response against infections, numerous studies have shown an important role of different TLRs in cancer, indicating these receptors as potential targets for cancer therapy. We previously demonstrated that the activation of TLR3 by the synthetic double-stranded RNA analogue poly I:C induces apoptosis of androgen-sensitive prostate cancer (PCa) LNCaP cells and, much less efficiently, of the more aggressive PC3 cell line. Therefore, in this study we selected LNCaP cells to investigate the mechanism of TLR3-mediated apoptosis and the in vivo efficacy of poly I:C-based therapy. We show that interferon regulatory factor-3 (IRF-3) signalling plays an essential role in TLR3-mediated apoptosis in LNCaP cells through the activation of the intrinsic and extrinsic apoptotic pathways. Interestingly, hardly any apoptosis was induced by poly I:C in normal prostate epithelial cells RWPE-1. We also demonstrate for the first time the direct anticancer effect of poly I:C as a single therapeutic agent in a well-established human androgen-sensitive PCa xenograft model, by showing that tumour growth is highly impaired in poly I:C-treated immunodeficient mice. Immunohistochemical analysis of PCa xenografts highlights the antitumour role of poly I:C in vivo both on cancer cells and, indirectly, on endothelial cells. Notably, we show the presence of TLR3 and IRF-3 in both human normal and PCa clinical samples, potentially envisaging poly I:C-based therapy for PCa. PMID:25444175

  9. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer

    DEFF Research Database (Denmark)

    Weischenfeldt, Joachim; Simon, Ronald; Feuerbach, Lars; Schlangen, Karin; Weichenhan, Dieter; Minner, Sarah; Wuttig, Daniela; Warnatz, Hans-Jörg; Stehr, Henning; Rausch, Tobias; Jäger, Natalie; Gu, Lei; Bogatyrova, Olga; Stütz, Adrian M; Claus, Rainer; Eils, Jürgen; Eils, Roland; Gerhäuser, Clarissa; Huang, Po-Hsien; Hutter, Barbara; Kabbe, Rolf; Lawerenz, Christian; Radomski, Sylwester; Bartholomae, Cynthia C; Fälth, Maria; Gade, Stephan; Schmidt, Manfred; Amschler, Nina; Haß, Thomas; Galal, Rami; Gjoni, Jovisa; Kuner, Ruprecht; Baer, Constance; Masser, Sawinee; von Kalle, Christof; Zichner, Thomas; Benes, Vladimir; Raeder, Benjamin; Mader, Malte; Amstislavskiy, Vyacheslav; Avci, Meryem; Lehrach, Hans; Parkhomchuk, Dmitri; Sultan, Marc; Burkhardt, Lia; Graefen, Markus; Huland, Hartwig; Kluth, Martina; Krohn, Antje; Sirma, Hüseyin; Stumm, Laura; Steurer, Stefan; Grupp, Katharina; Sültmann, Holger; Sauter, Guido; Plass, Christoph; Brors, Benedikt; Yaspo, Marie-Laure; Korbel, Jan O; Schlomm, Thorsten

    2013-01-01

    Early-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with "classical" (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursue...

  10. Long-term outcomes from dose-escalated image-guided intensity-modulated radiotherapy with androgen deprivation: encouraging results for intermediate- and high-risk prostate cancer

    Directory of Open Access Journals (Sweden)

    Wilcox SW

    2014-08-01

    Full Text Available Shea W Wilcox,1,4 Noel J Aherne,2,4 Linus C Benjamin,1 Bosco Wu,1 Thomaz de Campos Silva,3 Craig S McLachlan,4 Michael J McKay,3,5 Andrew J Last,1 Thomas P Shakespeare1–4 1North Coast Cancer Institute, Port Macquarie, NSW, Australia; 2North Coast Cancer Institute, Coffs Harbour, NSW, Australia; 3North Coast Cancer Institute, Lismore, NSW, Australia; 4The University of New South Wales, Rural Clinical School, Sydney, NSW, Australia; 5The University of Sydney, Sydney, NSW, Australia Purpose: Dose-escalated (DE radiotherapy in the setting of localized prostate cancer has been shown to improve biochemical disease-free survival (bDFS in several studies. In the same group of patients, androgen deprivation therapy (ADT has been shown to confer a survival benefit when combined with radiotherapy doses of up to 70 Gy; however, there is currently little long-term data on patients who have received high-dose intensity-modulated radiotherapy (IMRT with ADT. We report the long-term outcomes in a large cohort of patients treated with the combination of DE image-guided IMRT (IG-IMRT and ADT. Methods and materials: Patients with localized prostate cancer were identified from a centralized database across an integrated cancer center. All patients received DE IG-IMRT, combined with ADT, and had a minimum follow up of 12 months post-radiotherapy. All relapse and toxicity data were collected prospectively. Actuarial bDFS, metastasis-free survival, prostate cancer-specific survival, and multivariate analyses were calculated using the SPSS v20.0 statistical package. Results: Seven hundred and eighty-two eligible patients were identified with a median follow up of 46 months. Overall, 4.3% of patients relapsed, 2.0% developed distant metastases, and 0.6% died from metastatic prostate cancer. At 5-years, bDFS was 88%, metastasis-free survival was 95%, and prostate cancer-specific survival was 98%. Five-year grade 2 genitourinary and gastrointestinal toxicity was 2

  11. Paradoxical metastatic progression following 3 months of neo-adjuvant androgen suppression in the TROG 96.01 trial for men with locally advanced prostate cancer

    International Nuclear Information System (INIS)

    Purpose: In the TROG 96.01 trial 6 month neo-adjuvant androgen suppression (NAS) and radiotherapy (RT) for locally advanced prostate cancer prevented distant progressions (DPs) when compared to RT alone, but 3 months did not. We ask why? Methods: Between 1996 and 2000, 802 men with T2-4 N0 M0 prostate cancers received RT alone (0 month NAS) to 66 Gy, 3 months or 6 months NAS before RT. Interval hazards and cumulative incidences of DP were compared using competing risks methodology. Results: In the first 4 follow-up years 39, 40 and 26 DPs were diagnosed in subjects treated with 0, 3 and 6 month NAS, respectively. Compared with 0 month, significant reductions in PSA doubling time in subjects with DP occurred following 3 month NAS (p = 0.01), but a significant reduction (p = 0.01) and a near significant delay in DPs (p = 0.06) occurred after 6 month NAS. Subsequently 25, 20 and 11 DPs occurred in the three trial arms. After early secondary therapy for PSA or local progression 34, 19 and 12 DPs were diagnosed after median delays of almost 4 years. Conclusions: The data are consistent with the failure of 3 month NAS to prevent the progression of sub-clinical metastatic deposits already present before treatment

  12. Blockade of Androgen Markers Using a Novel Betasitosterol, Thioctic Acid and Carnitine-containing Compound in Prostate and Hair Follicle Cell-based Assays.

    Science.gov (United States)

    Chen, Li; Wang, Jiaolong; Mouser, Glen; Li, Yan Chun; Marcovici, Geno

    2016-06-01

    Androgenetic alopecia (AGA) affects approximately 70% of men and 40% of women in an age-dependent manner and is partially mediated by androgen hormones. Benign prostatic hyperplasia (BPH) similarly affects 50% of the male population, rising by 10% each decade. Finasteride inhibits 5-alpha reductase (5AR) and is used to treat both disorders, despite offering limited clinical benefits accompanied by significant adverse side effects. Building on our previous work demonstrating the efficacy of naturally derived 5AR inhibitors (such as stigmasterol and beta sitosterol), we hypothesize that targeting 5AR as well as inflammatory pathways may yield improved efficacy in AGA and BPH. Here we address these dual pathomechanisms by examining the potency of a novel composition using in vitro assays of representative cell lines for AGA (hair follicle dermal papilla cells) and BPH (LNCaP prostate cells), respectively. Exposure of cells to the novel test composition down-regulated mRNA expression profiles characteristic of both disease processes, which outperformed finasteride. Changes in mRNA expression were corroborated at the protein level as assessed by western blotting. These studies provide proof of concept that novel, naturally derived compositions simultaneously targeting 5AR and inflammatory mediators may represent a rational approach to treating AGA and BPH. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26990224

  13. SIRT1 IS REQUIRED FOR ANTAGONIST-INDUCED TRANSCRIPTIONAL REPRESSION OF ANDROGEN-RESPONSIVE GENES BY THE ANDROGEN RECEPTOR