Enzalutamide for the treatment of metastatic castration-resistant prostate cancer

Rodríguez‐Vida, Alejo; Galazi, Myria; Rudman, Sarah; Chowdhury, Simon; Sternberg, Cora N.

doi:10.2147/dddt.s69433

Cited by 51 publications

(41 citation statements)

References 44 publications

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“…Enzalutamide is a newly developed AR antagonist that has been approved by the US Food and Drug Administration (FDA) to treat metastatic CRPC in 2014. By preventing androgen binding to AR, enzalutamide inhibits the nuclear localization and transcriptional activity of AR (39). Despite the early clinical benefits, most patients eventually developed enzalutamide resistance due to reactivation of the AR signaling pathway by various mechanisms including AR truncation and point mutations (9).…”

Section: Resultsmentioning

confidence: 99%

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Chen

Farah

et al. 2016

Molecular Cancer Therapeutics

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Castration-resistant prostate cancer (CRPC) is the later stage of prostate cancer (PCa) when the disease has stopped responding to androgen deprivation therapy (ADT). It has been established that androgen receptor (AR) re-activation is responsible for the recurrence of PCa after ADT. Thus targeting different pathways that regulate AR stability and activity should be a promising strategy for treatment of CRPC. Heat shock proteins (HSPs) are chaperones that modify stability and activity of their client proteins. HSP90, a major player of the HSP family, regulates stabilities of many proteins, including AR and Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events. Further, HSP90 is overexpressed in different cancers, including PCa. Herein, we show that co-treatment of PCa with AR antagonist enzalutamide and HSP90 inhibitor leads to more severe cell death due to a synergistic reduction of AR protein. Interestingly, we show that overexpression of Plk1 rescued the synergistic effect and that co-targeting HSP90 and Plk1 also leads to more severe cell death. Mechanistically, we show that E3 ligase CHIP, in addition to targeting AR, is responsible for the degradation of Plk1 as well. These findings suggest that co-targeting HSP90 and some of its client proteins may be a useful strategy in treatment of CRPC.

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Section: Resultsmentioning

confidence: 99%

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Chen

Farah

et al. 2016

Molecular Cancer Therapeutics

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“…New drugs that prolong overall survival in patients with metastatic CRPC have been approved in recent years. These drugs include enzalutamide, a nonsteroidal secondgeneration androgen receptor inhibitor with heightened binding specificity that has been shown to be an effective and well-tolerated therapeutic option in both post-docetaxel and chemotherapy-naïve settings [7]. This compound provides a substantial survival benefit; however, not all patients with CRPC respond to this treatment [8].…”

Section: Introductionmentioning

confidence: 99%

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Xiang

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: Polyphyllin I (PPI), one of the steroidal saponins in Paris polyphylla, reportedly exhibits antitumor effects. However, the detailed mechanism underlying PPI, particularly in enhancing the effect of the androgen receptor inhibitor enzalutamide in controlling castration-resistant prostate cancer (CRPC) has not been explored. Methods: Cell viability and cell cycle distribution were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, respectively. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) expression was measured by quantitative real time-PCR (qRT-PCR). Western blot analysis was performed to determine the protein expression levels of MUC1, p65, and p50. Silencing of HOTAIR was evaluated using the siRNA procedure. The promoter activity of the MUC1 gene was determined using Secrete-Pair Dual Luminescence Assay Kit. Exogenous expression of HOTAIR, p65, and MUC1 was conducted by transient transfection assay. A xenograft tumor model in nude mice was used to further evaluate the effect of the combination of PPI and enzalutamide in vivo. Results: We showed that PPI significantly inhibited growth and induced cell cycle arrest in CRPC cells. PPI also decreased p65 and MUC1 protein expression and reduced HOTAIR expression. Exogenously expressed p65 resisted the PPI-inhibited expression of HOTAIR, whereas silenced HOTAIR reduced MUC1 protein but exerted no effect on the expression of p65 and p50 proteins. Conversely, exogenously expressed HOTAIR resisted the PPI-inhibited MUC1 protein expression, and excessive expression of MUC1 antagonized the PPI-inhibited cell growth. Notably, PPI combined with enzalutamide exerted a synergistic effect. Consistent with this finding, PPI inhibited tumor growth, HOTAIR expression, as well as p65 and MUC1 protein expressions in vivo. Conclusions: Our results indicate that PPI inhibits the growth of CRPC cells by inhibiting p65 protein and concomitantly reducing HOTAIR expression, thereby suppressing MUC1 gene expression. The novel regulatory interaction of p65 and HOTAIR converge in the inhibition of MUC1 expression and overall PPI response. The combination of PPI and enzalutamide exhibits synergy. This study reveals a novel mechanism underlying the synergistic inhibitory effect of PPI and enzalutamide on the growth of CRPC cells.

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“…The androgen receptor (AR) signaling pathway, which controls the growth of PCa cells, including those in CRPC, is a valid target for treatment (2). Consequently, current approaches to treat CRPC are to delay or replace treatment with cytotoxic agents (e.g., docetaxel) with androgen signaling inhibitors (ASIs), such as abiraterone and enzalutamide, instead (3,4). Despite success in targeting AR signaling pathway, resistance to these ASIs invariably develops (5).…”

Section: Introductionmentioning

confidence: 99%

Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer

Wang

Kong

et al. 2017

Molecular Cancer Therapeutics

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Olaparib is a FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data has also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of Olaparib in 22RV1, a BRCA1 deficient CRPC cell line, as well as in CRPC xenograft tumors. Mechanistically, monotherapy with Olaparib results in an override of the G1/S checkpoint, leading to high expression of Plk1, which attenuates Olaparib’s overall efficacy. In BRCA1 wild type C4-2 cells, Plk1 inhibition also significantly increases the efficacy of Olaparib in the presence of p53 inhibitor. Collectively, our findings not only implicate the critical role of Plk1 in PARPi resistance in BRCA-mutant CRPC cells, but also shed new light on the treatment of non-BRCA-mutant patient subgroups who might also respond favorably to PARPi.

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Enzalutamide for the treatment of metastatic castration-resistant prostate cancer

Cited by 51 publications

References 44 publications

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Cotargeting HSP90 and Its Client Proteins for Treatment of Prostate Cancer

Crosstalk of NF-κB/P65 and LncRNA HOTAIR-Mediated Repression of MUC1 Expression Contribute to Synergistic Inhibition of Castration-Resistant Prostate Cancer by Polyphyllin 1–Enzalutamide Combination Treatment

Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer

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