The Effect of a Histone Deacetylase Inhibitor (AR-42) on Canine Prostate Cancer Growth and Metastasis.
BACKGROUND
Canine prostate cancer (PCa) is an excellent preclinical model for human PCa. AR-42 is a histone deacetylase inhibitor (HDACi) developed at The Ohio State University that inhibits the proliferation of several cancers, including multiple myeloma, lung, and hepatocellular cancer. In this study, we investigated whether AR-42 would prevent or decrease. The growth and metastasis of a canine PCa (Ace-1 cells) to bone in vitro and in vivo.


METHODS
Proliferation, cell viability, invasion, and metastasis of a canine prostate cancer cell line (Ace-1) were measured following treatment with AR-42. Expression of anoikis resistance, epithelial-to-mesenchymal transition (EMT), and stem cell-related markers were also evaluated. To assess the efficacy of AR-42 on prevention of PCa metastasis to bone, Ace-1 cells were injected in the left cardiac ventricle of nude mice, mice were treated with AR-42, and the incidence and growth of bone metastasis were measured. Bioluminescence was performed to monitor the bone metastases in nude mice.


RESULTS
AR-42 inhibited the in vitro proliferation of Ace-1 cells in a time- and dose-dependent manner. The IC50concentration of AR-42 for Ace-1 cells was 0.42 μM after 24 hr of treatment. AR-42 induced apoptosis, decreased cell migration, and increased the stem cell properties of Ace-1 cells in vitro. AR-42 downregulated E-cadherin, N-cadherin, TWIST, MYOF, anoikis resistance, and osteomimicry genes, while it upregulated SNAIL, PTEN, FAK, and ZEB1 gene expression in Ace-1 cells. Importantly, AR-42 decreased the bioluminescence and incidence of bone metastasis in nude mice. In addition, AR-42 induced apoptosis and altered the tumor cell morphology to an irregular cell phenotype with condensed chromatin in the bone metastases.


CONCLUSIONS
AR-42 decreased PCa growth and bone metastasis, induced apoptosis, and downregulated osteomimicry genes in PCa cells in the bone microenvironment. Prostate 77:776-793, 2017. © 2017 Wiley Periodicals, Inc.
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.|Faculty of Veterinary Medicine, Department of Pathology, Benha University, Benha, Egypt.
Said M
SM
Elshafae
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
Nicole A
NA
Kohart
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
Lucas A
LA
Altstadt
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
Wessel P
WP
Dirksen
Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio.
Thomas J
TJ
Rosol
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000097:blood; D001859:Bone Neoplasms / Q000517:prevention & control / Q000556:secondary; D049109:Cell Proliferation / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D010654:Phenylbutyrates / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects*
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D056572:Histone Deacetylase Inhibitors; C529674:OSU-HDAC42 compound; D010654:Phenylbutyrates; D006655:Histone Deacetylases
AR-42; anoikis; canine; dog; metastasis; prostate cancer