Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration‐resistant prostate cancer

Guerrero, Julien; Alfaro, Iván E.; Gómez, Francisco Javier; Protter, Andrew A.; Bernales, Sebastián

doi:10.1002/pros.22674

Cited by 92 publications

(76 citation statements)

References 60 publications

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“…Enzalutamide's effect on HIF-1a-regulated gene expression is specifically targeted to VEGF, thus making VEGF a potential biomarker for assessing enzalutamide response; studies are underway to evaluate this effect in clinical treatment samples. Our results are consistent with a gene expression profiling study in LNCaP cells that indicate enzalutamide opposing agonist-induced changes in genes involved in processes such as angiogenesis (Guerrero et al, 2013). Moreover, a recent clinical study found that nonspecific HIF-1a inhibitors (digoxin, metformin, angiotensin-2 receptor blockers) appear to increase progression-free survival and reduce the risk of developing CRPC and metastases in patients on continuous androgen deprivation therapy (Ranasinghe et al, 2014).…”

Section: Discussionsupporting

confidence: 90%

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

et al. 2015

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Enzalutamide is a potent second-generation androgen receptor (AR) antagonist with activity in metastatic castrate-resistant prostate cancer (CRPC). Although enzalutamide is initially effective, disease progression inevitably ensues with the emergence of resistance. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Given that both AR and hypoxia inducible factor-1 a (HIF-1a) are key regulators of these processes, dual targeting of both signaling axes represents an attractive therapeutic approach. Crosstalk of the AR and HIF-1a signaling pathways were examined in prostate cancer cell lines (LNCaP, 22Rv1) with assays measuring the effect of androgen and hypoxia on AR-dependent and hypoxia-inducible gene transcription, protein expression, cell proliferation, and apoptosis. HIF-1a inhibition was achieved by siRNA silencing HIF-1a or via chetomin, a disruptor of HIF-1a-p300 interactions. In prostate cancer cells, the gene expression of AR targets (KLK3, FKBP5, TMPRSS2) was repressed by HIFsignaling; conversely, specific HIF-1a target expression was induced by dihydrotestosterone-mediated AR signaling. Treatment of CRPC cells with enzalutamide or HIF-1a inhibition attenuated AR-regulated and HIF-1a-mediated gene transcription. The combination of enzalutamide and HIF-1a inhibition was more effective than either treatment alone. Similarly, the combination also reduced vascular endothelial growth factor protein levels. HIF-1a siRNA synergistically enhanced the inhibitory effect of enzalutamide on cell growth in LNCaP and enzalutamide-resistant 22Rv1 cells via increased enzalutamide-induced apoptosis. In conclusion, the combination of enzalutamide with HIF-1a inhibition resulted in synergistic inhibition of AR-dependent and genespecific HIF-dependent expression and prostate cancer cell growth.

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Section: Discussionsupporting

confidence: 90%

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

et al. 2015

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“…In contrast, Enz does not stimulate AR nuclear translocation and DNA binding (Tran et al, 2009;Guerrero et al, 2013). To test whether the partial Enz chemical scaffold would mobilize AR to the chromatin, we employed ChIP using C4-2 cells treated with androgen, Enz, SAHA, and compound 2-75.…”

Section: Resultsmentioning

confidence: 99%

Hybrid Enzalutamide Derivatives with Histone Deacetylase Inhibitor Activity Decrease Heat Shock Protein 90 and Androgen Receptor Levels and Inhibit Viability in Enzalutamide-Resistant C4-2 Prostate Cancer Cells

Rosati¹,

Chen²,

Patki³

et al. 2016

Mol Pharmacol

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Histone deacetylase inhibitors (HDACIs) can disrupt the viability of prostate cancer (PCa) cells through modulation of the cytosolic androgen receptor (AR) chaperone protein heat shock protein 90 (HSP90). However, toxicities associated with their pleiotropic effects could contribute to the ineffectiveness of HDACIs in PCa treatment. We designed hybrid molecules containing partial chemical scaffolds of enzalutamide and suberoylanilide hydroxamic acid (SAHA), with weakened intrinsic pan-HDACI activities, to target HSP90 and AR in enzalutamideresistant PCa cells. The potency of the new molecules, compounds 2-75 [4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide] and 1005 [(E)-3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenyl)-N-hydroxyacrylamide], as inhibitors of nuclear and cytosolic histone deacetylases was substantially lower than that of SAHA in cell-free and in situ assays. Compounds 2-75 and 1005 antagonized gene activation by androgen without inducing chromatin association of AR. Enzalutamide had no effect on the levels of AR or HSP90, whereas the hybrid compounds induced degradation of both AR and HSP90, similar to (compound 1005) or more potently than (compound 2-75) SAHA. Similar to SAHA, compounds 2-75 and 1005 decreased the level of HSP90 and induced acetylation in a predicted approximately 55 kDa HSP90 fragment. Compared with SAHA, compound 2-75 induced greater hyperacetylation of the HDAC6 substrate a-tubulin. In contrast with SAHA, neither hybrid molecule caused substantial hyperacetylation of histones H3 and H4. Compounds 2-75 and 1005 induced p21 and caused loss of viability in the enzalutamide-resistant C4-2 cells, with efficacies that were comparable to or better than SAHA. The results suggest the potential of the new compounds as prototype antitumor drugs that would downregulate HSP90 and AR in enzalutamide-resistant PCa cells with weakened effects on nuclear HDACI targets.

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“…Enzalutamide treatment caused a regression of tumors in a CRPC xenograft model in vivo [22]. Subsequent study revealed that enzalutamide induces apoptosis in PCa cells overexpressing AR, suggesting a mechanism that could contribute to the reduction in tumor volume [35]. In contrast, bicalutamide treatment initially induced tumor growth inhibition in the xenograft model, but the effect was not sustained and tumors resumed growing at the same rate as in untreated animals.…”

Section: Expert Opinionmentioning

confidence: 92%

“…Enzalutamide inhibits multiple steps of AR signaling: binding of androgens to AR, AR nuclear translocation and association of AR with DNA. Guerrero et al reported that gene expression profiling in LNCaP cells indicated that enzalutamide opposes agonist-induced changes in genes involved in processes such as cell adhesion, angiogenesis and apoptosis [35]. These results suggested that the molecular effects of enzalutamide on AR signaling and gene expression contribute to its effectiveness in treating CRPC and represent mechanistic advantages of enzalutamide over the first-generation antiandrogens.…”

Section: Preclinical Studiesmentioning

confidence: 93%

Enzalutamide: looking back at its preclinical discovery

Kim

2014

Expert Opinion on Drug Discovery

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The landscape of CRPC has changed dramatically over the last few years, as new agents with proven benefit in overall survival have been approved. Compared to the average time of 10 - 15 years for a new drug to go from pre-clinical discovery to registration, enzalutamide obtained FDA approval in < 6 years after its initial characterization. Enzalutamide, a targeted agent of the androgen-AR axis, has shown promising results in CRPC and is generally well tolerated. However, drug resistance inevitably emerges is a severe limitation. The authors believe that further clinical studies that look at its use as either a combinational or sequential therapy could help to address these concerns.

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Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration‐resistant prostate cancer

Abstract: These results indicate that enzalutamide efficiently inhibits AR signaling, and we suggest that its lack of AR agonist activity may be important for these effects.

Cited by 92 publications

References 60 publications

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

Dual Targeting of the Androgen Receptor and Hypoxia-Inducible Factor 1α Pathways Synergistically Inhibits Castration-Resistant Prostate Cancer Cells

Hybrid Enzalutamide Derivatives with Histone Deacetylase Inhibitor Activity Decrease Heat Shock Protein 90 and Androgen Receptor Levels and Inhibit Viability in Enzalutamide-Resistant C4-2 Prostate Cancer Cells

Enzalutamide: looking back at its preclinical discovery

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