Antiandrogens prevent stable DNA-binding of the androgen receptor

Farla, Pascal; Hersmus, Remko; Trapman, Jan; Houtsmuller, Adriaan B.

doi:10.1242/jcs.02546

Cited by 99 publications

(98 citation statements)

References 62 publications

(119 reference statements)

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“…The antiandrogen properties of several phenothiazine derivatives (SI Table 2) seem to corroborate this assumption. The ability of the D4 ligand to induce translocation of the AR from the cytoplasm into the nucleus also suggests that its antiandrogen activity is mechanis- tically similar to that of hydroxyflutamide (45) and bicalutamide (Figs. 2 A and 3) (45), both of which induce AR translocation from the cytoplasm to the nucleus.…”

Section: Discussionmentioning

confidence: 97%

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

Bisson

Cheltsov

Bruey-Sédano

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico ''drug repurposing'' procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.androgen receptor ͉ drug design ͉ prostate cancer C urrent approaches for discovery of novel chemical leads against a molecular target rely heavily on high-throughput screening (HTS) and to a lesser extent on virtual ligand screening (VLS) techniques. HTS has provided rapid lead identification for numerous drug targets (1-8); however, HTS also has major drawbacks, including a significant level of false positives and false negatives and low hit rates for many targets (9). Successful leads from HTS can also suffer from poor bioavailability and unwanted toxicity profiles of compounds. These problems result partially from the nature of the chemical libraries used for HTS. Furthermore, because the pharmacological properties of most compound libraries are largely unknown, there is an additional high risk that optimization of hits identified with HTS will not be sufficient for their evolution into real drugs.In contrast, retrospective analysis of marketed drugs reveals that their physicochemical and structural properties are clustered around preferred values and scaffolds (10). In addition, some chemical motifs are associated with high biological activity and often confer activity against more than one target/receptor (11-16). These motifs have been referred to as ''privileged structures'' (11). These observations lead to an assumption that the chemical space of potential drugs is limited. Consequently, currently marketed...

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Section: Discussionmentioning

confidence: 97%

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

Bisson

Cheltsov

Bruey-Sédano

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…This antagonistic effect relies on its capacity to recruit co-repressor complexes to the AR (46). In addition, inhibitory actions of bicalutamide on AR DNA binding activity have also being reported (47). Consequently, bicalutamide is considered to mainly antagonize the AR-mediated transcriptional (genomic) effects of androgens.…”

Section: Discussionmentioning

confidence: 99%

Androgen Induction of Prostate Cancer Cell Invasion Is Mediated by Ezrin

Chuan

Pang

Cedazo-Minguez

et al. 2006

Journal of Biological Chemistry

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Ezrin is a key signaling molecule that regulates cell survival, adhesion migration, and invasion. We have previously shown that ezrin is regulated by androgen in rat prostate and that its expression is increased in prostate cancer and in prostate intraepithelial neoplasia. We have used the androgen-sensitive cell line LNCaP-FGC to investigate the role of ezrin in androgeninduced cell invasion. We found that androgen treatment of LNCaP-FGC cells induces ezrin expression, an effect that is inhibited by the androgen receptor antagonist, bicalutamide. In addition, androgen treatment induces the phosphorylation of ezrin in Thr-567 and Tyr-353 in a sequential manner. This is mediated through protein kinase C ␣ and Src tyrosine kinase, respectively. Androgen treatment induces the translocation of both protein kinase C ␣ and ezrin to the cell membrane and their association. Inhibition of ezrin function using short interference RNA or the overexpression of T567A and Y353F-ezrin mutants significantly reduces androgen-induced Matrigel invasion but does not affect cell proliferation or cell adhesion. Matrigel invasion of the androgen-insensitive prostate cancer cell lines PC-3 and LNCaP-R is also dependent on ezrin. In summary, we have shown that androgens regulate ezrin at transcriptional and posttranscriptional levels. Hormonal regulation of ezrin phosphorylation is required for androgen-induced cell invasion. Prostate cancer (PCa)2 remains a leading cause of mortality worldwide. Despite important progress in the early diagnosis of prostate neoplasias through the measurement of prostate-specific antigen levels, ϳ10% of newly diagnosed patients have some evidence of locally advanced PCa and 5% already have distant metastasis at the time of diagnoses (1-3). Postmortem analysis of deaths attributed to PCa reveals that most subjects have evidence of metastatic disease (4). Some treatment alternatives exist with curative potential in the case of locally advanced PCa (5-7). In contrast, patients with evidence of distant metastasis have a very poor prognosis and no curative treatment exists (8).Androgen ablation therapy in its many modalities has been a mainstay in the treatment of prostatic adenocarcinoma. In general, androgen deprivation induces remission in 80 -90% of men with advanced PCa and results in a median progressionfree survival of 12-33 months. This period is usually followed by the emergence of an androgen-independent PCa resulting in a median overall survival of 23-37 months. In metastatic PCa disease, androgen ablation is also the first line of treatment. Androgen ablation in combination with external beam radiotherapy or prostatectomy delays disease progression and results in significant survival advantage when compared with radiation therapy or prostatectomy alone (5-7, 9).It is not entirely clear how hormone refractory cancer develops (10, 11). One hypothesis is that some of the mechanisms that are normally under androgen control become constitutively active in androgen-independent cells. This is supported by ...

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“…In fact, this modulation is one of the key mechanisms essential for the functional role of nuclear hormone receptors (Stenoien et al, 2001;Schaaf and Cidlowski, 2003;Stavreva et al, 2004;Elbi et al, 2004b;Farla et al, 2005;Rayasam et al, 2005). In vivo FRAP has been used to study the dynamic properties of chromatin proteins and that the FRAP recovery kinetics of chromatin proteins are directly related to their chromatin-binding properties (Lefebvre et al, 1991;Fragoso et al, 1998;Lever et al, 2000;Kimura and Cook, 2001;Kimura et al, 2002;Maruvada et al, 2003;Phair et al, 2004;Becker et al, 2005;Chen et al, 2005).…”

Section: Chromatin-remodeling Complexes Have Distinct Kinetic Propertmentioning

confidence: 99%

Chromatin Remodeling Complexes Interact Dynamically with a Glucocorticoid Receptor–regulated Promoter

Johnson

Elbi

Parekh

et al. 2008

MBoC

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Brahma (BRM) and Brahma-related gene 1 (BRG1) are the ATP-dependent catalytic subunits of the SWI/SNF family of chromatin-remodeling complexes. These complexes are involved in essential processes such as cell cycle, growth, differentiation, and cancer. Using imaging approaches in a cell line that harbors tandem repeats of stably integrated copies of the steroid responsive MMTV-LTR (mouse mammary tumor virus-long terminal repeat), we show that BRG1 and BRM are recruited to the MMTV promoter in a hormone-dependent manner. The recruitment of BRG1 and BRM resulted in chromatin remodeling and decondensation of the MMTV repeat as demonstrated by an increase in the restriction enzyme accessibility and in the size of DNA fluorescence in situ hybridization (FISH) signals. This chromatin remodeling event was concomitant with an increased occupancy of RNA polymerase II and transcriptional activation at the MMTV promoter. The expression of ATPase-deficient forms of BRG1 (BRG1-K-R) or BRM (BRM-K-R) inhibited the remodeling of local and higher order MMTV chromatin structure and resulted in the attenuation of transcription. In vivo photobleaching experiments provided direct evidence that BRG1, BRG1-K-R, and BRM chromatin-remodeling complexes have distinct kinetic properties on the MMTV array, and they dynamically associate with and dissociate from MMTV chromatin in a manner dependent on hormone and a functional ATPase domain. Our data provide a kinetic and mechanistic basis for the BRG1 and BRM chromatin-remodeling complexes in regulating gene expression at a steroid hormone inducible promoter. INTRODUCTIONThe eukaryotic genome is organized into higher order chromatin structures in the nucleus. The regulation of eukaryotic gene expression in the context of chromatin is a complex event and is essential for numerous cellular processes (Lemon and Tjian, 2000;Orphanides and Reinberg, 2002;Labrador and Corces, 2002;Maniatis and Reed, 2002;Felsenfeld and Groudine, 2003;Roberts and Orkin, 2004). Maintenance, establishment, and modification of global chromatin organization and local chromatin structure are modulated by a large number of chromatin-binding proteins that generate transcriptionally permissive or repressed chromatin domains in response to environmental stimuli (Workman and Kingston, 1998;Peterson and Workman, 2000;Jones and Kadonaga, 2000;Wu and Grunstein, 2000;Wolffe and Hansen, 2001;Becker et al., 2002). The association of linker histones and nonhistone and heterochromatin-specific proteins such as high mobility group proteins and HP1 play key roles in the generation of higher order chromatin structures (Arents et al., 1991; Luger et al., 1997;Bustin, 1999;Eissenberg and Elgin, 2000;Hill, 2001;Thomas and Travers, 2001;Woodcock and Dimitrov, 2001;Grewal and Elgin, 2002;Bianchi and Agresti, 2005;Bustin et al., 2005;Verschure et al., 2005). The stearically restricted environment presented by chromatin is in part overcome by multisubunit protein complexes that enzymatically regulate chromatin structure. These complexes can e...

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Antiandrogens prevent stable DNA-binding of the androgen receptor

Cited by 99 publications

References 62 publications

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

Androgen Induction of Prostate Cancer Cell Invasion Is Mediated by Ezrin

Chromatin Remodeling Complexes Interact Dynamically with a Glucocorticoid Receptor–regulated Promoter

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