The preclinical development of bicalutamide: pharmacodynamics and mechanism of action

Furr, B. J. A.; Tucker, Howard

doi:10.1016/s0090-4295(96)80003-3

Cited by 89 publications

(71 citation statements)

References 37 publications

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“…To confirm our results acquired on the basis of a genetic repression model, we used bicalutamide (5 μM), a pharmacological inhibitor of AR 27. As anticipated, bicalutamide totally repressed the increase in myotube size induced by testosterone and urolithin B ( Figure 3C and 3D).…”

Section: Resultssupporting

confidence: 75%

Urolithin B, a newly identified regulator of skeletal muscle mass

Rodriguez

Pierre

Naslain

et al. 2017

J cachexia sarcopenia muscle

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BackgroundThe control of muscle size is an essential feature of health. Indeed, skeletal muscle atrophy leads to reduced strength, poor quality of life, and metabolic disturbances. Consequently, strategies aiming to attenuate muscle wasting and to promote muscle growth during various (pathological) physiological states like sarcopenia, immobilization, malnutrition, or cachexia are needed to address this extensive health issue. In this study, we tested the effects of urolithin B, an ellagitannin‐derived metabolite, on skeletal muscle growth.MethodsC2C12 myotubes were treated with 15 μM of urolithin B for 24 h. For in vivo experiments, mice were implanted with mini‐osmotic pumps delivering continuously 10 μg/day of urolithin B during 28 days. Muscle atrophy was studied in mice with a sciatic nerve denervation receiving urolithin B by the same way.ResultsOur experiments reveal that urolithin B enhances the growth and differentiation of C2C12 myotubes by increasing protein synthesis and repressing the ubiquitin–proteasome pathway. Genetic and pharmacological arguments support an implication of the androgen receptor. Signalling analyses suggest a crosstalk between the androgen receptor and the mTORC1 pathway, possibly via AMPK. In vivo experiments confirm that urolithin B induces muscle hypertrophy in mice and reduces muscle atrophy after the sciatic nerve section.ConclusionsThis study highlights the potential usefulness of urolithin B for the treatment of muscle mass loss associated with various (pathological) physiological states.

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Section: Resultssupporting

confidence: 75%

Urolithin B, a newly identified regulator of skeletal muscle mass

Rodriguez

Pierre

Naslain

et al. 2017

J cachexia sarcopenia muscle

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“…Moreover, the AR was shown to be destabilized in the presence of bic (Waller et al 2000). All these observations explain why bic can decrease androgen-induced gene expression and reduce the weight of rat ventral prostate and seminal vesicles after oral administration (Furr & Tucker 1996).…”

Section: Mechanism Of Action Of Antiandrogensmentioning

confidence: 80%

Androgen receptor antagonists for prostate cancer therapy

Helsen¹,

Broeck²,

Voet³

et al. 2014

Endocrine-Related Cancer

123

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Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

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“…In addition, the existence of an independent transmembrane androgen receptor has been proposed, although such a molecule has not being identified yet. Because bicalutamide has low affinity for SHBG (45) and is structurally unrelated to androgens it is unlikely they share additional receptor molecules other than 3 A. Flores-Morales, unpublished observations. the AR.…”

Section: Discussionmentioning

confidence: 95%

“…The mechanisms used by bicalutamide to promote cell invasion in vitro are poorly understood. Bicalutamide is a non-steroidal compound that binds the ligand binding domain of the AR (45). In contrast to androgens, bicalutamide binding renders the AR transcriptionally inactive.…”

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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The preclinical development of bicalutamide: pharmacodynamics and mechanism of action

Cited by 89 publications

References 37 publications

Urolithin B, a newly identified regulator of skeletal muscle mass

Urolithin B, a newly identified regulator of skeletal muscle mass

Androgen receptor antagonists for prostate cancer therapy

Androgen Induction of Prostate Cancer Cell Invasion Is Mediated by Ezrin

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