BACKGROUNDS/AIMS: Bromodomain-containing protein 4 (BRD4) overexpression 
participates in prostate cancer progression by enhancing the transcriptional 
activity and expression of several key oncogenes. AZD5153 is a novel BRD4 
inhibitor.
METHODS: Prostate cancer cells were treated with AZD5153. Cell survival was 
tested by MTT assay and clonogenicity assay. Cell proliferation was tested by 
[H3] DNA incorporation assay. Cell apoptosis was tested by caspase-3/-9 activity 
assay, Histone DNA ELISA assay, Annexin V FACS assay and TUNEL staining assay. 
Cell cycle progression was tested by propidium iodide (PI) FACS assay. Signaling 
was tested by Western blotting assay. The nude mice PC-3 xenograft model was 
applied to test AZD5153's activity in vivo.
RESULTS: AZD5153 inhibited proliferation and survival of established and primary 
prostate cancer cells. AZD5153 induced apoptosis activation and cell cycle 
arrest in prostate cancer cells. AZD5153 was non-cytotoxic to the prostate 
epithelial cells. AZD5153 downregulated BRD4 targets (cyclin D1, Myc, Bcl-2, 
FOSL1 and CDK4) in PC-3 and primary prostate cancer cells. Further studies show 
that AKT could be the primary resistance factor of AZD5153. Pharmacological 
inhibition or genetic depletion of AKT induced BRD4 downregulation, sensitizing 
AZD5153-induced cytotoxicity in PC-3 cells. In vivo, AZD5153 oral administration 
inhibited PC-3 xenograft tumor growth in nude mice. Its anti-tumor activity was 
further enhanced with co-treatment of the AKT specific inhibitor MK-2206.
CONCLUSION: Together, our results indicate a promising therapeutic value of the 
novel BRD4 inhibitor AZD5153 against prostate cancer cells.