ABSTRACT
PURPOSE: The role of androgen receptor (AR) signaling in bladder cancer (BCa) is not fully characterized. This study aimed to delineate the role of AR signaling in BCa and to determine whether the combination of AR inhibitor, Enzalutamide (Enz), and Cisplatin (Cis) efficiently inhibit the growth of BCa cells. METHODS: AR expression was determined in 89 human urothelial BCa specimens by immunohistochemistry. A panel of BCa cell lines was treated with Cis, Enz, or a combination of both (Enzâ¯+â¯Cis). We determined the expression of AR, changes in apoptotic signaling, DNA damage, and analyzed effect on epithelial mesenchymal transformation markers. RESULT: AR expression was detected in 61.4% of tumors from male BCa patients. Inhibition of AR signaling by Enz effectively inhibited the growth of AR+ BCa cells by inducing apoptosis (26%) in AR+ TCCSUP (P = 0.0201) and J82 (15%, Pâ¯=â¯0.0386) cells. Interestingly, Enzâ¯+â¯Cis synergistically inhibited the proliferation of BCa cells even at low concentrations by inducing proapoptotic signaling in AR+ BCa cells. Invasive and migratory potential of TCCSUP and J82 cells were reduced with Enzâ¯+â¯Cis treatment, and associated with down-regulation of mesenchymal markers. CONCLUSIONS: A high percentage of the bladder tumors from male patients in our cohort expressed AR. The combination of Enz and Cis synergistically inhibited growth of BCa cells more efficiently than single agent alone. This supports the rationale for future investigation of AR antagonists in combination with standard chemotherapy in MIBC.
Subject(s)
Androgen Receptor Antagonists/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Cisplatin/therapeutic use , Receptors, Androgen/metabolism , Urinary Bladder Neoplasms/drug therapy , Androgen Receptor Antagonists/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Benzamides , Carcinoma, Transitional Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , Cohort Studies , DNA Damage/drug effects , Drug Resistance, Neoplasm , Drug Synergism , Female , Humans , Male , Middle Aged , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic use , Signal Transduction/drug effects , Treatment Outcome , Urinary Bladder/pathology , Urinary Bladder Neoplasms/pathology , Urothelium/pathologyABSTRACT
We recently demonstrated that AKT activation plays a role in prostate cancer progression and inhibits the pro-apoptotic function of FOXO3a and Par-4. AKT inhibition and Par-4 induction suppressed prostate cancer progression in preclinical models. Here, we investigate the chemopreventive effect of the phytonutrient Withaferin A (WA) on AKT-driven prostate tumorigenesis in a Pten conditional knockout (Pten-KO) mouse model of prostate cancer. Oral WA treatment was carried out at two different doses (3 and 5 mg/kg) and compared to vehicle over 45 weeks. Oral administration of WA for 45 weeks effectively inhibited primary tumor growth in comparison to vehicle controls. Pathological analysis showed the complete absence of metastatic lesions in organs from WA-treated mice, whereas discrete metastasis to the lungs was observed in control tumors. Immunohistochemical analysis revealed the down-regulation of pAKT expression and epithelial-to-mesenchymal transition markers, such as ß-catenin and N-cadherin, in WA-treated tumors in comparison to controls. This result corroborates our previous findings from both cell culture and xenograft models of prostate cancer. Our findings demonstrate that the daily administration of a phytonutrient that targets AKT activation provides a safe and effective treatment for prostate cancer in a mouse model with strong potential for translation to human disease.
