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


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.
Department of Urology, University of California-Los Angeles, Los Angeles, California.
David R
DR
Li
Department of Urology, University of California-Los Angeles, Los Angeles, California; Eli and Edythe Broad Stem Cell Research Center, University of California-Los Angeles, Los Angeles, California.
Hanwei
H
Zhang
Molecular Biology Institute, University of California-Los Angeles, Los Angeles, California.
Elizabeth
E
Peek
Urology Center, First Hospital of Jilin University, Changchun, People's Republic of China.
Song
S
Wang
Department of Biostatistics, University of California-Los Angeles, Los Angeles, California.
Lin
L
Du
Department of Biostatistics, University of California-Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, California.
Gang
G
Li
Department of Urology, University of California-Los Angeles, Los Angeles, California; Eli and Edythe Broad Stem Cell Research Center, University of California-Los Angeles, Los Angeles, California; Molecular Biology Institute, University of California-Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, California. Electronic address: aichin@ucla.edu.
Arnold I
AI
Chin
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases; D006801:Humans; D010654:Phenylbutyrates / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D006655:Histone Deacetylases; D002945:Cisplatin
apoptosis; chromatin; cisplatin; histone deacetylase inhibitors; urinary bladder neoplasms