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Androgen Depletion (androgen + depletion)

Distribution by Scientific Domains

Medical Sciences	100%

Selected Abstracts

Molecular modelling of the androgen receptor axis: rational basis for androgen receptor intervention in androgen-independent prostate cancer

BJU INTERNATIONAL, Issue 2005
ROBERT J. FLETTERICK
Androgen depletion in combination with antiandrogenic agents is initially highly effective for treating prostate cancer, and is the recommended treatment for more advanced or higher-grade tumours. However, many tumours eventually become insensitive to androgens, even though the androgen receptor (AR) continues to be expressed. Computational chemistry combined with structural analysis of nuclear receptors and determination of binding affinities of natural and designed coregulators (coactivators and corepressors) provides the theoretical framework for the rational design of novel therapeutic agents directed at the AR. Adding alternative groups to various sites throughout the receptor can alter the conformation of the molecule and its functional binding with coactivators or corepressors. Possible molecules can be identified thoroughly and systematically using intelligent high-throughput screening and FASTrack chemistry (three-dimensional crystallography). Applying these techniques should eventually result in therapeutic agents for androgen-independent prostate cancer that can block binding of AR coactivators while simultaneously increasing binding of AR corepressors. [source]

Androgen action on human skin , from basic research to clinical significance

EXPERIMENTAL DERMATOLOGY, Issue 2004
Christos C. Zouboulis
Abstract:, Androgens affect several functions of the human skin, such as sebaceous gland growth and differentiation, hair growth, epidermal barrier homeostasis and wound healing. Their effects are mediated by binding to nuclear androgen receptors. Androgen activation and deactivation are mainly intracellular events. They differ from cell type to cell type and between cells at different locations. The major circulating androgens, dehydroepiandrosterone sulfate and androstenedione, are predominantly produced in the adrenal glands, and testosterone and 5,-dihydrotestosterone are mainly synthesized in the gonads. Testosterone in women and 5,-dihydrotestosterone in both genders are also synthesized in the skin. Skin cells express all androgen metabolizing enzymes required for the independent cutaneous synthesis of androgens and the development of hyperandrogenism-associated conditions and diseases, such as seborrhea, acne, hirsutism and androgenetic alopecia. The major thrust of drug design for the treatment of androgen-associated disorders has been directed against several levels of androgen function and metabolism. Partial effectiveness has only been achieved either by androgen depletion, inhibition of androgen metabolism or blockade of the androgen receptor. [source]

PKC-mediated secretion of death factors in LNCaP prostate cancer cells is regulated by androgens

MOLECULAR CARCINOGENESIS, Issue 3 2009
Liqing Xiao
Abstract Activation of PKC, in androgen-dependent LNCaP prostate cancer cells leads to apoptosis via the activation of p38 MAPK and JNK cascades. We have recently shown that treatment of LNCaP cells with phorbol 12-myristate 13-acetate (PMA) leads to a PKC,-mediated autocrine release of death factors, including the cytokines TNF, and TRAIL, and that conditioned medium (CM) collected from PMA-treated LNCaP cells promotes the activation of the extrinsic apoptotic cascade. Interfering with this autocrine loop either at the level of factor release or death receptor activation/signaling markedly impaired the PMA apoptotic response. In the present study we show that this PKC,-dependent autocrine mechanism is greatly influenced by androgens. Indeed, upon androgen depletion, which down-regulates PKC, expression, TNF, and TRAIL mRNA induction and release by PMA are significantly diminished, resulting in a reduced apoptogenic activity of the CM and an impaired ability of the CM to activate p38 MAPK and JNK. These effects can be rescued by addition of the synthetic androgen R1881. Furthermore, RNAi depletion of the androgen-receptor (AR) from LNCaP cells equally impaired PMA responses, suggesting that PKC-mediated induction of death factor secretion and apoptosis in LNCaP prostate cancer cells are highly sensitive to hormonal control. © 2008 Wiley-Liss, Inc. [source]

Role of coordinated molecular alterations in the development of androgen-independent prostate cancer: an in vitro model that corroborates clinical observations

BJU INTERNATIONAL, Issue 1 2006
YAN SHI
OBJECTIVE To investigate the role of potential downstream targets of HER-2/neu, including the cell-cycle regulator p27, proliferation-associated protein Ki-67, apoptosis inhibitor Bcl-2, and signal-transduction molecule Akt (which is associated with cell survival), as the development of androgen-independent prostate cancer (AIPC) in patients who are initially responsive to androgen-ablation therapy (AAT) is a significant clinical problem. PATIENTS AND METHODS Earlier studies showed that high levels of HER-2/neu tyrosine kinase receptor expression as assessed by immunohistochemistry were significantly associated with the development of AIPC, and we hypothesised that HER-2/neu overexpression provides an alternative proliferative stimulus upon androgen depletion. We established a unique clinical model system, comprising patients who received no AAT, or who had preoperative AAT, or those with advanced tumours resistant to AAT. To test our hypothesis in vitro, we stably transfected full-length HER-2/neu cDNA in androgen-responsive LNCaP cells and examined the effects of HER-2/neu overexpression on cell proliferation, apoptosis, androgen-receptor activation, and Akt phosphorylation upon androgen deprivation by using immunohistochemistry and Western blot technique. RESULTS p27 expression was initially induced on exposure to AAT, and significantly decreased in AIPC (P < 0.001). There was also a significant increase in the Ki-67 index in AIPC (P = 0.001). Elevated Bcl-2 expression was closely associated with AAT (P = 0.002), suggesting that Bcl-2 expression is induced on initial exposure to AAT. Further, Bcl-2 expression was highest in hormone-resistant cancers (P < 0.001). Using the HER-2/neu transfected cell-line model, we confirmed the mechanistic basis of the clinical observations which elucidate the pathway leading to HER-2/neu-mediated androgen independence. On androgen deprivation, the HER-2/neu transfected cells had higher proliferation rates, lower G1 arrest, inhibited p27 up-regulation, a lower apoptotic index, and higher Bcl-2, prostate-specific antigen and phosphorylated Akt expression than the mock-transfected LNCaP cells. CONCLUSION This study suggests that prostate cancer cells undergo a series of coordinated changes after exposure to AAT, which eventually result in the development of androgen independence. Further, in support of previous results, it appears that a major factor in this process is the induction of HER-2/neu overexpression, which occurs after initial exposure to AAT. HER-2/neu may contribute to the development of androgen independence through: (i) maintaining cell proliferation; (ii) inhibiting apoptosis; and/or (iii) inducing AR activation in a ligand-independent fashion. These effects may be mediated, at least in part, through activation of the PI3K/Akt pathway. [source]