Determination of androgen receptor degradation enhancer ASC-J9® in mouse sera and organs with liquid chromatography tandem mass spectrometry

Soh, Shu Fang; Huang, Chiung‐Kuei; Lee, Soo Ok; Xu, Defeng; Yeh, Shuyuan; Li, Jun; Yong, Eu Leong; Gong, Yiwei; Chang, Chawnshang

doi:10.1016/j.jpba.2013.08.020

Cited by 20 publications

(12 citation statements)

References 15 publications

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“…Furthermore, we found ASC-J9 ® , a novel AR degradation enhancer (52), functions in a manner similar to AR-siRNA to partially reverse the T cell-induced BCa cell invasion by reducing AR expression, which is in agreement with early studies showing ASC-J9 ® decreases BCa progression via targeting AR signaling (4, 15, 53). …”

Section: Discussionsupporting

confidence: 89%

Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals

Qiu

Jiang

et al. 2016

Molecular Cancer Therapeutics

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The tumor microenvironment impacts tumor progression and individual cells, including CD4+ T cells, have been detected in bladder cancer (BCa) tissues. The detailed mechanism how these T cells were recruited to the BCa tumor and their impact on BCa progression, however, remains unclear. Using a human clinical BCa sample survey and in vitro co-culture system, we found that BCa has a greater capacity to recruit T cells than surrounding normal bladder tissues. The consequences of higher levels of recruited T cells in BCa included increased BCa metastasis. Mechanism dissection revealed that infiltrating T cells might function through secreting the cytokine IL-1 which increases the recruitment of T cells to BCa and enhances the BCa androgen receptor (AR) signaling that results in increased BCa cell invasion via up-regulation of HIF-1α/VEGFa expression. Interruption of the IL-1→AR→HIF-1α→VEGFa signals with inhibitors of HIF-1α or VEGFa partially reversed the enhanced-BCa cell invasion. Finally, in vivo mouse models of xenografted BCa T24 cells with CD4+ T cells confirmed in vitro co-culture studies and concluded that infiltrating CD4+ T cells can promote BCa metastasis via modulation of the IL-1→AR→HIF-1α→VEGFa signaling. Future clinical trials using small molecules to target this newly identified signaling pathway may facilitate the development of new therapeutic approaches to better suppress BCa metastasis.

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Section: Discussionsupporting

confidence: 89%

Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals

Qiu

Jiang

et al. 2016

Molecular Cancer Therapeutics

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“…In addition, our data have strong clinical implication since current therapies designed to target the induced HIF2α/VEGF signals due to mutant or suppressed VHL ( via promoter hyper-methylation) only yield limited efficacy in select RCC patients [ 6 ]. Therefore, the development new therapies against AR either with AR-siRNAs or the newly developed AR degradation enhancer ASC-J9 ® [ 37 , 41 , 42 ] or introducing miR-145 mimic shall provide an alternative therapeutic option to better suppress the induced HIF2α/VEGF signals.…”

Section: Discussionmentioning

confidence: 99%

“…Another potential advantage of targeting AR-suppressed miR-145 signals may come from the profound AR effects to suppress RCC progression that suppression of HIF2α-VEGF signal alone may not be able to have, and early studies using ASC-J9 ® to suppress AR-mediated prostate cancer/bladder cancer progression all resulted in reasonable efficacy with little side effects in tested mice [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status

et al. 2015

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Mutational inactivation of the VHL tumor suppressor plays key roles in the development of renal cell carcinoma (RCC), and mutated VHL-mediated VEGF induction has become the main target for the current RCC therapy. Here we identified a signal pathway of VEGF induction by androgen receptor (AR)/miRNA-145 as a new target to suppress RCC progression. Mechanism dissection revealed that AR might function through binding to the androgen receptor element (ARE) located on the promoter region of miRNA-145 to suppress p53's ability to induce expression of miRNA-145 that normally suppresses expression of HIF2α/VEGF/MMP9/CCND1. Suppressing AR with AR-shRNA or introducing exogenous miRNA-145 mimic can attenuate RCC progression independent of VHL status. MiR-145 mimic in preclinical RCC orthotopic xenograft mouse model revealed its efficacy in suppression of RCC progression. These results together identified signals by AR-suppressed miRNA-145 as a key player in the RCC progression via regulating HIF2α/VEGF/MMP9/CCND1 expression levels. Blockade of the newly identified signal by AR inhibition or miRNA-145 mimics has promising therapeutic benefit to suppress RCC progression.

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“…To prove the key roles of our newly identified Enz/ Malat1 / AR-v7 axis in the development of Enz-resistance in the in-vivo mouse model and seek new therapeutic approaches to better suppress EnzR-PCa, we used our newly developed EnzR cell lines to test the efficacy of targeting Malat1 and AR-v7 with Malat1 -siRNA or AR-v7 degradation enhancer ASC-J9 ® [11–15]. The results revealed that silencing Malat1 expression by Malat1 -siRNA or degrading AR-v7 by ASC-J9 ® suppressed the growth of EnzR cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9 ® to Suppress Enzalutamide-resistant Prostate Cancer Progression

et al. 2017

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Background While androgen-deprivation-therapy with the recently developed anti-androgen enzalutamide (Enz) shows promising therapeutic benefits in men with metastatic castration-resistant prostate cancer (PCa), many patients develop resistance to Enz, which may involve the induction of the androgen receptor (AR) splicing variant 7 (AR-v7). Objective Our aim is to identify the mechanisms responsible for AR-v7 production and to develop novel preclinical approaches to suppress the Enz-resistant (EnzR) PCa. Design, setting, and participants We established EnzR-PCa cell lines and examined the long noncoding RNA Malat1 (Malat1) function in conferring Enz resistance. We also examined the in vivo effects of Malat1 short interfering RNA and the AR-v7 degradation enhancer, ASC-J9®. Outcome measurements and statistical analysis Enz resistance and expression of Malat1 and AR-v7. All statistical comparisons were analyzed with a t-test or one way analysis of variance followed by t-test. Results and limitations We demonstrated that Malat1 is indispensable for Enz-induced AR-v7 production in VCaP and EnzR-C4-2 cells. We observed increased AR-v7 and Malat1 expression in our established EnzR-PCa cell lines and in some PCa patients who received Enz treatment. Targeting the Malat1/AR-v7 axis resulted in altering the PCa resistance to androgen deprivation therapy with Enz. The limitation of this study includes the small sample size from the same human patients before and after receiving Enz treatment. Conclusions Targeting the Malat1/AR-v7 axis via Malat1-short interfering RNA or AR-v7 degradation enhancer ASC-J9® in EnzR-PCa cell lines and mouse models suppressed EnzR-PCa progression. Patient summary Androgen deprivation therapy-enzalutamide treatment may not be the best choice for prostate cancer patients who have higher expression of the Malat1/ androgen receptor splicing variant 7 axis, and new therapies using Malat1-short interfering RNA or ASC-J9® may be developed in the future to better suppress enzalutamide-resistant prostate cancer.

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Determination of androgen receptor degradation enhancer ASC-J9® in mouse sera and organs with liquid chromatography tandem mass spectrometry

Cited by 20 publications

References 15 publications

Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals

Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals

Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status

Preclinical Study using Malat1 Small Interfering RNA or Androgen Receptor Splicing Variant 7 Degradation Enhancer ASC-J9 ® to Suppress Enzalutamide-resistant Prostate Cancer Progression

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