ASC-J9® increases the bladder cancer chemotherapy efficacy via altering the androgen receptor (AR) and NF-κB survival signals.

backgroundThe current chemotherapy regimens may extend survival for patients with metastatic bladder cancer (BCa) for a few months, but eventually most patients succumb to disease because they develop resistance to their chemotherapy.

methodsTCGA human clinical sample survey and urothelial tumor tissue microarrays (TMAs) were applied to investigate the expression of androgen receptor (AR) and NF-κB. Multiple BCa cell lines were used to test chemotherapy's efficacy via multiple assays including XTT, flow cytometry, TUNEL, and BrdU incorporation. The effects of the AR degradation enhancer, ASC-J9®, combined with various chemotherapy reagents were examined both in vivo and in vitro.

resultsWe unexpectedly found that in muscle-invasive BCa (miBCa) the signals of both the AR and NF-κB were increased via a TCGA sample survey. Results from multiple approaches revealed that targeting these two increased signals by combining various chemotherapeutic agents, including Cisplatin, Doxorubicin or Mitomycin C, with ASC-J9® led to increase the therapeutic efficacy. The combined therapy increases the expression of the pro-apoptosis BAX gene and cell cycle inhibitor p21 gene, yet suppresses the expression of the pro-survival BCL2 gene in miBCa cells. Preclinical studies using an in vivo mouse model with xenografted miBCa cells confirmed in vitro cell line data showing that treatment with ASC-J9® combined with Cisplatin can result in suppressing miBCa progression better than Cisplatin alone.

conclusionsTogether, these results support a novel therapeutic approach via combining Cisplatin with ASC-J9® to better suppress the progression of miBCa.