Synergy of Histone-Deacetylase Inhibitor AR-42 with Cisplatin in Bladder Cancer

• Published in: The Journal of urology Vol. 194; no. 2; pp. 547 - 555
• Main Authors: Li, David R, Zhang, Hanwei, Peek, Elizabeth, Wang, Song, Du, Lin, Li, Gang, Chin, Arnold I
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2015
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Cell Line, Tumor; Cell Proliferation - drug effects; chromatin; cisplatin; Cisplatin - pharmacology; Drug Synergism; histone deacetylase inhibitors; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases; Humans; Phenylbutyrates - pharmacology; urinary bladder neoplasms; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - pathology; Urology; Nod- scid IL-2Rgamma null; IC 50; sodium butyrate; NSG; TSA; trichostatin A; CI; CK; apoptosis; cytokeratin; VA; valproic acid; chromatin; histone deacetylase; NaB; propidium iodide; percent of maximal inhibitory concentration; urinary bladder neoplasms; PI; cisplatin; combination index; histone deacetylase inhibitors; HDAC; IC50
• ISSN: 0022-5347; 1527-3792
• DOI: 10.1016/j.juro.2015.02.2918

Purpose Cisplatin based chemotherapy regimens form the basis of systemic bladder cancer treatment, although they show limited response rates and efficacy. Recent molecular analysis of bladder cancer revealed a high incidence of mutations in chromatin regulatory genes, suggesting a therapeutic avenue for histone deacetylase inhibitors. We investigated the ability of the novel histone deacetylase inhibitor AR-42 to synergize with cisplatin in preclinical models of bladder cancer. Materials and Methods We assessed the ability of the pan-histone deacetylase inhibitor AR-42 with and without cisplatin to destroy bladder cancer cells by survival and apoptosis assays in vitro, and by growth and differentiation in an in vivo xenograft model. We also assessed the response to the bladder cancer stem cell population by examining the effect of AR-42 on the CD44+ CD49f+ population with and without cisplatin. Synergy was calculated using combination indexes. Results The AR-42 and cisplatin combination synergistically destroyed bladder cancer cells via apoptosis and it influenced tumor growth and differentiation in vivo. When tested in the CD44+ CD49f+ bladder cancer stem cell population, AR-42 showed greater efficacy with and without cisplatin. Conclusions AR-42 may be an attractive novel histone deacetylase inhibitor with activity against bladder cancer. Its efficacy in bladder cancer stem cells and synergy with cisplatin warrant further clinical investigation. Our in vitro and animal model studies provide preclinical evidence that AR-42 may be administered in conjunction with cisplatin based chemotherapy to improve the treatment of bladder cancer in patients.