Eighty Years of Targeting Androgen Receptor Activity in Prostate Cancer: The Fight Goes on (original) (raw)
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The androgen receptor: a potential target for therapy of prostate cancer
Steroids, 2004
The androgen receptor plays a pivotal role in the prostate. Its primary function is to provide responsive gene products for differentiation and growth, but under abnormal conditions it contributes to the development of prostate cancer. The goal of this review is to elucidate the molecular functions of the androgen receptor and its role in prostate cancer. Initially the function of the androgen receptor will be described. Next, the clinical diagnosis, epidemiological impact, and treatments of androgen-dependent and -independent prostate cancer will be discussed. Finally we will examine how the mechanism of androgen action has played a role in the translation of new therapies and how this may influence future treatment modalities of prostate cancer.
Advances in androgen receptor targeted therapy for prostate cancer
Journal of Cellular Physiology, 2014
Prostate Cancer (PCa) is the second leading cause of cancer death in men. Current research findings suggest that the androgen receptor (AR) and its signaling pathway contribute significantly to the progression of metastatic PCa. The AR is a ligand activated transcription factor, where androgens such as testosterone (T) and dihydroxytestosterone (DHT) act as the activating ligands. However in many metastatic PCa, the AR functions promiscuously and is constitutively active through multiple mechanisms. Inhibition of enzymes that take part in androgen synthesis or synthesizing antiandrogens that can inhibit the AR are two popular methods of impeding the androgen receptor signaling axis; however, the inhibition of androgen-independent activated AR function has not yet been fully exploited. This article focuses on the development of emerging novel agents that act at different steps along the androgen-AR signaling pathway to help improve the poor prognosis of PCa patients.
Androgen receptor as a target in androgen-independent prostate cancer
Urology, 2002
Prostate cancer is dependent on androgen stimulation mediated by the androgen receptor (AR), a member of the steroid hormone receptor family of ligand-dependent nuclear receptors. Most patients respond to standard androgen ablation therapies, but virtually all patients eventually relapse with disease that has been termed hormone-refractory or androgen-independent disease. Efforts to use AR antagonists, such as flutamide or bicalutamide, to enhance responses to primary androgen ablation therapy or to treat androgenindependent prostate cancer have been disappointing, which has diminished enthusiasm for more aggressive or alternative methods to block AR function. However, many lines of evidence indicate that AR function contributes to tumor cell survival after androgen ablation and to growth of androgen-independent prostate cancer. This article outlines a number of mechanisms that may contribute to AR activity in androgenindependent prostate cancer, including AR amplification, AR mutation, altered expression of AR coactivator and corepressor proteins, and activation of other pathways that can enhance AR function. Understanding the mechanisms responsible for AR function in androgen-independent prostate cancer should allow the more rational development of antagonists that can enhance the efficacy of androgen ablation therapies. UROLOGY 60 (Suppl 3A): 132-139, 2002.
Androgen receptor - an update of mechanisms of action in prostate cancer
Urological Research, 2000
Androgen receptor (AR), a key nuclear transcription factor in the prostate gland, is expressed in all histological types and stages of prostate cancer. The AR regulates proliferation of prostate cancer cells by stimulation of cyclin-dependent kinases. However, in some prostate tumors AR stimulates expression of cell cycle inhibitors, thus leading to down-regulation of cellular proliferation. Androgens, by activation of the AR, control dierentiation of prostate cells and synthesis of neutral lipids. There are several mechanisms by which prostate cancer cells adapt to an environment with low androgen supply during endocrine therapy. The AR expression and activity increase in several cell lines that are used as an in vitro model for monitoring changes during long-term androgen ablation. Mutant ARs are of importance for monitoring the natural course of the disease and for determining the response to anti-androgens in metastatic lesions from prostatic carcinoma. In addition, AR activity is up-regulated by various stimulators of intracellular protein kinases. Current research eorts are focused on elucidation of function of AR coregulatory proteins, coactivators and corepressors. Their inappropriate expression and/or function might critically in¯uence cellular events in advanced carcinoma of the prostate. It is hoped that information on these coregulatory proteins will serve as a basis for a more ecient pharmacological inhibition of the AR in advanced carcinoma of the prostate.
International Journal of Molecular Sciences
Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites...
Androgen receptors in prostate cancer
Endocrine Related Cancer, 2002
The androgen receptor (AR), a transcription factor that mediates the action of androgens in target tissues, is expressed in nearly all prostate cancers. Carcinoma of the prostate is the most frequently diagnosed neoplasm in men in industrialized countries. Palliative treatment for non-organ-confined prostate cancer aims to down-regulate the concentration of circulating androgen or to block the transcription activation function of the AR. AR function during endocrine therapy was studied in tumor cells LNCaP subjected to long-term steroid depletion; newly generated sublines could be stimulated by lower concentrations of androgen than parental cells and showed up-regulation of AR expression and activity as well as resistance to apoptosis. Androgenic hormones regulate the expression of key cell cycle regulators, cyclin-dependent kinase 2 and 4, and that of the cell cycle inhibitor p27. Inhibition of AR expression could be achieved by potential chemopreventive agents flufenamic acid, res...
Recent discoveries and developments of Androgen Receptor based therapy for Prostate Cancer
MedChemComm
The main focus of the review is to discuss the discoveries and developments of various therapies for prostate cancer. The AR has played an important role in Prostate cancer growth and functions. In this review, we discussed several groups of drugs that have sparingly good anti-cancer activities, also have a similar structure and behaviour. Recent new-generation AR antagonists, Enzalutamide (MDV3100) has approved for the treatment of advanced/metastatic Prostate Cancer. The Nonsteroidal antiandrogens represent an important class of molecules acting as either antagonists or agonists. Recently, many therapeutic agents for Prostate cancer have been approved that target the androgen receptor and reduces the Prostate tumour growth. The strong response to this new use of Enzalutamide provides a viable, less toxic alternative to chemotherapy. The current status of Prostate cancer drugs have been discussed here, but it is evident that much work for improvements in respect of efficacy, reduction of side effects and treatment strategies are to be addressed.
Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications
Cells
Around 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensit...