Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer

Liu, Chengfei; Armstrong, Cameron M.; Lou, Wei; Lombard, Alan P.; Cucchiara, Vito; Gu, Xinwei; Yang, Joy C.; Nadiminty, Nagalakshmi; Pan, Chong‐Xian; Evans, Christopher P.; Gao, Allen C.

doi:10.1158/1535-7163.mct-16-0912

Cited by 54 publications

(35 citation statements)

References 43 publications

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“…Several studies have addressed whether there could be an interaction between AR signaling activity and the sensitivity of bicalutamide, which is the most widely used AR antagonist . We therefore examined the effect of protocadherin B9 on bicalutamide resistance.…”

Section: Resultsmentioning

confidence: 99%

“…Although patients initially show a favorable response to bicalutamide treatment, PCa eventually acquires bicalutamide resistance. Several factors have been shown to be involved in bicalutamide resistance . However, the mechanism of bicalutamide resistance is not fully understood.…”

Section: Discussionmentioning

confidence: 99%

“…It is well known that the androgen receptor (AR) plays a key role in the initiation and progression of PCa . Androgen deprivation therapy (ADT), including bicalutamide treatment, has been widely used as the first‐line treatment for PCa . Although patients who receive ADT initially exhibit a favorable response, PCa eventually develops resistance to bicalutamide and progresses to castration‐resistant PCa (CRPC), which is an aggressive disease that is associated with metastasis and death .…”

Section: Introductionmentioning

confidence: 99%

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Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients

Sekino

Oue

Mukai³

et al. 2018

The Prostate

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Background Prostate cancer (PCa) is a common malignancy worldwide and is the second leading cause of cancer death in men. The standard therapy for advanced PCa is androgen deprivation therapy (ADT). Although ADT, including bicalutamide treatment, is initially effective, resistance to bicalutamide frequently occurs and leads to the development of castration‐resistant PCa. Thus, clarifying the mechanisms of bicalutamide resistance is urgently needed. We designed this study to assess the expression and function of PCDHB9, which encodes the protocadherin B9 protein. Methods The expression of PCDHB9 was determined using immunohistochemistry and a qRT‐PCR. The effects of the overexpression or knockdown of PCDHB9 on cell growth, migration, adhesion were evaluated. To evaluate the PCDHB9‐mediated effects in PCa, we performed a gene expression analysis using DU145 transfected with PCDHB9. We examined the effects of PCDHB9 inhibition on bicalutamide resistance. Results The qRT‐PCR revealed that the expression of PCDHB9 was much higher in PCa than that in non‐neoplastic prostate tissues. In 152 clinically localized PCa cases immunohistochemistry showed that 59% of PCa cases were positive for protocadherin B9. A Kaplan‐Meier analysis showed that the high expression of protocadherin B9 was associated with PSA recurrence after radical prostatectomy. A functional analysis showed that PCDHB9 modulated cell migration and adhesion. We also found that PCDHB9 induced the expression of ITGB6 based on a gene expression analysis. The effect of PCDHB9 inhibition on bicalutamide sensitivity was examined using MTT assays. The IC50 value of PCDHB9 siRNA‐transfected PCa cells was significantly lower than that of negative control siRNA‐transfected cells. Furthermore, immunohistochemical staining of protocadherin B9 in 74 PCa patients who were treated with androgen depletion therapy, including bicalutamide treatment, demonstrated that the high expression of protocadherin B9 was significantly associated with poor overall survival. Conclusions PCDHB9 plays an important role in the progression of PCa and bicalutamide resistance. Collectively, our results suggest that PCDHB9 targeted therapy may be more effective than bicalutamide alone.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients

Sekino

Oue

Mukai³

et al. 2018

The Prostate

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“…More experiments need to be conducted Our data demonstrated a potentially synergistic inhibitory effect of the combination of PPI and enzalutamide on CRPC cell growth and relevant molecular targets. Enzalutamide combined with other agents exhibited even greater inhibitory effects on CRPC cells via multiple molecular mechanisms [53][54][55][56]. In addition, PPI was reported to reverse epithelialmesenchymal transition, decrease the expression levels of interleukin-6 and signal transducer activator of transcription 3 (STAT3) in the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib-resistant lung cancer cells.…”

Section: Discussionmentioning

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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“…AR‐FL/AR‐V7 protein degradation is under clinical investigation as a treatment strategy for CR‐PCa . CYP17 lyase inhibitor galeterone and non‐steroidal hydroxybenzamide niclosamide act as AR degradation enhancers in PCa and both are in clinical trials . While the data as yet to be published, galeterone was unable to increase progression‐free survival compared to enzalutamide in a Phase III trial .…”

Section: Discussionmentioning

confidence: 99%

Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

et al. 2018

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Background Prostate cancer (PCa) is diagnosed at the highest rate of all non‐cutaneous male cancers in the United States. The androgen‐dependent (AD) transcription factor, androgen receptor (AR), drives PCa—but inhibiting AR or androgen biosynthesis induces remission for only a short time. At which point, patients acquire more aggressive castration‐resistant (CR) disease with re‐activated AR‐dependent signaling. To combat treatment resistance, down‐regulating AR protein expression has been considered as a potential treatment strategy for CR‐PCa. Methods AD‐ and CR‐PCa cell lines were treated with the well‐tolerated FDA‐approved oral medicine, riluzole. Expression of full‐length or wild‐type AR (AR‐FL) and constitutively active AR‐splice variant 7 (AR‐V7) was assessed by immunoblotting. AR‐FL/AR‐V7 activity was measured using qRT‐PCR of AR‐target genes. Cytoplasmic [Ca2+] levels were measured using a fluorescent Ca2+ indicator microplate assay. Markers of the endoplasmic reticulum stress (ERS) pathway and autophagy were assessed by immunoblotting. Direct interaction between AR and selective autophagy receptor p62 was demonstrated by co‐immunoprecipitation. Results We demonstrate that riluzole downregulates AR‐FL, mutant ARs, and AR‐V7 proteins expression by protein degradation through ERS pathway and selective autophagy. Riluzole also significantly inhibited AR transcription activity by decreasing its target genes expression (PSA, TMPRSS2, and KLK2). Conclusions We provide key mechanistic insights by which riluzole exerts its anti‐tumorigenic effects and induces AR protein degradation via ERS pathways. Our findings support the potential utility of riluzole for treatment of PCa.

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Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer

Cited by 54 publications

References 43 publications

Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients

Protocadherin B9 promotes resistance to bicalutamide and is associated with the survival of prostate cancer patients

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

Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

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