Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models.
BACKGROUND
Histone deacetylase (HDAC) inhibitors represent a novel class of therapeutic agents with antitumor activity currently in clinical development. In this study, we tested the biological effects of the HDAC inhibitor MS-275 in various pre-clinical prostate cancer models both in'vitro and in vivo.


METHODS
In vitro cell proliferation XTT assay and protein expression analysis by Western blot were performed. In vivo tumor growth assessment in subcutaneous, orthotopic, and transgenic mouse models were conducted.


RESULTS
MS-275 significantly upregulated histone H3 acetylation and p21 gene expression in human prostate cancer cell lines. MS-275 exerted growth arrest in PC-3 and LNCaP cells, and induced cell death in DU-145 cells. Prostate specific antigen protein levels were increased by MS-275 in LAPC4 cell line. In vivo, MS-275 inhibited the growth of DU-145, LNCaP, and PC-3 in subcutaneous xenografts. MS-275 had also a significant inhibition of PC-3 cells growth in a mouse intratibial model. Molecular analysis showed increased histone acetylation and p21 expression in tumor samples from MS-275-treated mice. In transgenic adenocarcinoma of mouse prostate (TRAMP) mice, long-term treatment of MS-275 slowed the progression of prostate carcinomas with significant reduction in cell proliferation.


CONCLUSIONS
Taken together, these data support the clinical testing of MS-275 for the treatment of prostate cancer.
Qian
David Z
DZ
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Wei
Yong-Feng
YF
Wang
Xiaofei
X
Kato
Yukihiko
Y
Cheng
Linzhao
L
Pili
Roberto
R
D000230:Adenocarcinoma / Q000737:chemistry / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D011725:Pyridines / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; C118739:entinostat; D017430:Prostate-Specific Antigen