Androgen receptor (AR) degradation enhancer ASC-J9 ® in an FDA-approved formulated solution suppresses castration resistant prostate cancer cell growth
| Autor: | Defeng Xu, Fu-Ju Chou, Qiaoxia Zhang, Chawnshang Chang, Rachel Yang, Jie Ding, Max A. Cheng, Shuyuan Yeh, Keliang Wang, Gonghui Li |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Confluency Stromal cell Chemistry Cell growth Cell medicine.disease Androgen receptor 03 medical and health sciences Prostate cancer 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Oncology Cell culture 030220 oncology & carcinogenesis medicine Cancer research Clonogenic assay |
| Zdroj: | Cancer Letters. 417:182-191 |
| ISSN: | 0304-3835 |
| Popis: | ASC-J9® is a recently-developed androgen receptor (AR)-degradation enhancer that effectively suppresses castration resistant prostate cancer (PCa) cell proliferation and invasion. The optimal half maximum inhibitory concentrations (IC50) of ASC-J9® at various PCa cell confluences (20%, 50%, and 100%) were assessed via both short-term MTT growth assays and long-term clonogenic proliferation assays. Our results indicate that the IC50 values for ASC-J9® increased with increasing cell confluency. The IC50 values were significantly decreased in PCa AR-positive cells compared to PCa AR-negative cells or in normal prostate cells. This suggests that ASC-J9® may function mainly via targeting the AR-positive PCa cells with limited unwanted side-effects to suppress the surrounding normal prostate cells. Mechanism dissection indicated that ASC-J9® might function via altering the apoptosis signals to suppress the PCa AR-negative PC-3 cells. Preclinical studies using multiple in vitro PCa cell lines and an in vivo mouse model with xenografted castration-resistant PCa CWR22Rv1 cells demonstrated that ASC-J9® has similar AR degradation effects when dissolved in FDA-approved solvents, including DMSO, PEG-400:Tween-80 (95:5), DMA:Labrasol:Tween-80 (10:45:45), and DMA:Labrasol:Tween-20 (10:45:45). Together, results from preclinical studies suggest a potential new therapy with AR-degradation enhancer ASC-J9® may potentially be ready to be used in human clinical trials in order to better suppress PCa at later castration resistant stages. |
| Databáze: | OpenAIRE |
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