Androgen receptor antagonists for prostate cancer therapy

Helsen, Christine; Broeck, Thomas Van den; Voet, Arnout; Prekovic, Stefan; Poppel, Hendrik Van; Joniau, Steven; Claessens, Frank

doi:10.1530/erc-13-0545

Cited by 125 publications

(95 citation statements)

References 107 publications

(115 reference statements)

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“…Bicalutamide is a synthetic, non-steroidal, AR antagonist used in the treatment of several cancers252627. We tested the effect of this AR inhibitor, bicalutamide, on osteosarcoma cells.…”

Section: Resultsmentioning

confidence: 99%

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

Liao

Sassi

Halvorsen

et al. 2017

Sci Rep

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Osteosarcoma is the most common bone cancer in children and adolescents. Previously, we have found that cyclin-dependent kinase 11 (CDK11) signaling was essential for osteosarcoma cell growth and survival. Subsequently, CDK11 siRNA gene targeting, expression profiling, and network reconstruction of differentially expressed genes were performed between CDK11 knock down and wild type osteosarcoma cells. Reconstructed network of the differentially expressed genes pointed to the AR as key to CDK11 signaling in osteosarcoma. CDK11 increased transcriptional activation of AR gene in osteosarcoma cell lines. AR protein was highly expressed in various osteosarcoma cell lines and patient tumor tissues. Tissue microarray analysis showed that the disease-free survival rate for patients with high-expression of AR was significantly shorter than for patients with low-expression of AR. In addition, AR gene expression knockdown via siRNA greatly inhibited cell growth and viability. Similar results were found in osteosarcoma cells treated with AR inhibitor. These findings suggest that CDK11 is involved in the regulation of AR pathway and AR can be a potential novel prognostic marker and therapeutic target for osteosarcoma treatment.

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“…Bicalutamide is a synthetic, non-steroidal, AR antagonist used in the treatment of several cancers252627. We tested the effect of this AR inhibitor, bicalutamide, on osteosarcoma cells.…”

Section: Resultsmentioning

confidence: 99%

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

Liao

Sassi

Halvorsen

et al. 2017

Sci Rep

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“…Surgery and radiotherapy are successful treatments for early and localized tumors (3,4), but the preferred therapy for advanced PCa is androgen-deprivation therapy. The majority of patients eventually develop androgen-independent or hormone-refractory PCa (5), and chemotherapy is the only remaining option for advanced hormone-refractory PCa (6). Further investigation into the molecular mechanisms underlying the tumorigenesis and development of PCa, and the consequential development of novel targeted therapeutics, is required.…”

Section: Introductionmentioning

confidence: 99%

Prostate cancer cell proliferation is suppressed by microRNA‑3160‑5p via targeting of F‑box and WD repeat domain containing 8

et al. 2018

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Abstract. MicroRNAs (miRNAs/miRs), which are endogenous non-coding single-stranded RNAs 19-25 nucleotides in length, regulate gene expression by blocking translation or transcription repression. The present study revealed that miR-3160-5p was widely expressed in prostate cancer cells by reverse transcription-quantitative polymerase chain reaction. There was a negative association between the expression of miR-3160-5p and F-box and WD repeat domain containing 8 (Fbxw8) in prostate cancer DU145 cells. A luciferase activity assay was used to verify that Fbxw8 is the target of miR-3160-5p. In the present study, using MTT assay and cell cycle analysis, it was demonstrated that DU145 cell proliferation was repressed and the cell cycle was arrested in the G 2 /M cell cycle phase with upregulation of miR-3160-5p. Subsequent studies demonstrated that miR-3160-5p regulated the progression of the cell cycle in DU145 prostate cancer cells when the expression levels of phosphorylated cell division cycle (CDC)2, CDC25C and cyclin B1 were directly inhibited. Taken together, these findings revealed the mechanism underlying the role of miR-3160-5p in regulating the proliferation of DU145 cells and indicated that miR-3160-5p may serve as a promising novel therapeutic tool for prostate cancer.

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“…Enzalutamide acts as a direct competitor for dihydrotestosterone (DHT) binding to the ligand-binding pocket of the AR. In addition, it reduces the binding of the AR to DNA, and inhibits the recruitment of AR coactivators (4). Importantly, enzalutamide significantly prolonged the survival of men with mCRPC after chemotherapy by a median of 4.8 months in comparison with the placebo group (5).…”

Section: Introductionmentioning

confidence: 99%

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

Prekovic

Royen

Voet

et al. 2016

Molecular Cancer Therapeutics

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Treatment-induced mutations in the ligand-binding domain of the androgen receptor (AR) are known to change antagonists into agonists. Recently, the F877L mutation has been described to convert enzalutamide into an agonist. This mutation was seen to co-occur in the endogenous AR allele of LNCaP cells, next to the T878A mutation. Here, we studied the effects of enzalutamide on the F877L and T878A mutants, as well as the double-mutant AR (F877L/T878A). Molecular modeling revealed favorable structural changes in the double-mutant AR that lead to a decrease in steric clashes for enzalutamide. Ligand-binding assays confirmed that the F877L mutation leads to an increase in relative binding affinity for enzalutamide, but only the combination with the T878A mutation resulted in a strong agonistic activity. This correlated with changes in coregulator recruitment and chromatin interactions. Our data show that enzalutamide is only a very weak partial agonist of the AR F877L, and a strong partial agonist of the double-mutant AR.

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Androgen receptor antagonists for prostate cancer therapy

Cited by 125 publications

References 107 publications

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

Androgen receptor is a potential novel prognostic marker and oncogenic target in osteosarcoma with dependence on CDK11

Prostate cancer cell proliferation is suppressed by microRNA‑3160‑5p via targeting of F‑box and WD repeat domain containing 8

The Effect of F877L and T878A Mutations on Androgen Receptor Response to Enzalutamide

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