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Histone deacetylase inhibitor, suberoylanilide hydroxamic acid (Vorinostat, SAHA) profoundly inhibits the growth of human pancreatic cancer cells
Author(s) -
Kumagai Takashi,
Wakimoto Naoki,
Yin Dong,
Gery Sigal,
Kawamata Norihiko,
Takai Noriyuki,
Komatsu Naoki,
Chumakov Alexy,
Imai Yasufumi,
Koeffler H.Phillip
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22558
Subject(s) - vorinostat , cancer research , sodium butyrate , pancreatic cancer , histone deacetylase inhibitor , histone deacetylase , cell cycle , trichostatin a , biology , cancer cell , cell growth , microbiology and biotechnology , cyclin b1 , cyclin d1 , chemistry , cyclin dependent kinase 1 , apoptosis , histone , cancer , cell culture , biochemistry , gene , genetics
Tumor suppressor genes are often silenced in human cancer; this can occur by transcriptional repression by deacetylation in the promoter regions, mediated by histone deacetylase (HDAC). HDAC inhibitors can block cancer cell growth by restoring expression of tumor suppressor genes. In this study, we investigated the effects of a HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) on pancreatic cancer cells. SAHA inhibited the growth of 6 pancreatic cancer cell lines in a dose‐dependent manner as measured by MTT and clonogenic assays (ED 50 ≈10 −6 M) associated with induction of apoptosis, G2 cell cycle arrest and also induced differentiation as indicated by morphology and increased expression of cytokeratin 7. It increased expression of p21 WAF1 (independent of the mutational status of p53), C/EBPα, RARα and E‐cadherin; these genes have been associated with decreased proliferation in other cancers. SAHA decreased cyclin B1 expression; this cyclin normally promotes progression through G2 of the cell cycle. SAHA mediated acetylation of histone H3 globally, as well as, associated with the p21 WAF1 promoter, as measured by chromatin immunoprecipitation. SAHA also decreased levels of c‐myc and cyclin D1, independent of an active β‐catenin pathway. In further studies, the combination of SAHA and an inhibitor of DNA methylation, 5‐Aza‐2′‐deoxycytidine, had an enhanced antiproliferative effect on pancreatic cancer cells. In summary, SAHA inhibited the growth of human pancreatic cancer cells by inducing apoptosis, differentiation and cell cycle arrest, as well as increase in the expression of several tumor suppressor genes. SAHA is a novel, promising therapeutic agent for human pancreatic cancers. © 2007 Wiley‐Liss, Inc.