ASC-J9® suppresses castration resistant prostate cancer cell growth.

What is it about?

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), and DMA:Labrasol:Tween-80 (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.

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Why is it important?

ASCJ9® targeting PCa through both AR-dependent and AR-independent mechanistic pathways. IC50 values were found to be significantly lower in AR-positive cells in comparison to AR-negative cells, suggesting the importance of ASC-J9® as an AR-degradation enhancer. ASC-J9® could also function via an AR-independent apoptotic pathway. From pre-clinical mouse models, we found that ASC-J9® has similar AR-degradation effects when dissolved in various FDA-approved solvents. Our results provide support for future human clinical trials of ASC-J9®, which could suppress prostate cancer at the castration resistant stage.