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Activity of the histone deacetylase inhibitor belinostat (PXD101) in preclinical models of prostate cancer
Author(s) -
Qian Xiaozhong,
Ara Gulshan,
Mills Evan,
LaRochelle William J.,
Lichenstein Henri S.,
Jeffers Michael
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.23243
Subject(s) - histone deacetylase , cancer research , prostate cancer , medicine , histone deacetylase inhibitor , cytotoxic t cell , cell growth , prostate , pharmacology , cancer , in vitro , histone , chemistry , biochemistry , dna
Histone deacetylase inhibitors (HDACi) represent a promising new class of anticancer agents. In the current investigation, we examined the activity of the HDACi belinostat in preclinical models of prostate cancer. In vitro proliferation assays demonstrated that belinostat potently inhibited the growth of prostate cancer cell lines (IC 50 < 1.0 μM) and was cytotoxic to these cells. Washout experiments indicated that exposure to belinostat for relatively short periods of time (<12 hr) induced suboptimal growth‐inhibition and that cells exposed to 1.0 μM belinostat for 48 hr retained the capacity for regrowth following drug withdrawal, while cells exposed to 4.0 μM belinostat were irreversibly growth‐inhibited. Cell cycle analyses demonstrated that belinostat induced G2/M arrest and increased the percentage of cells with subG1 DNA content, thus confirming the growth‐inhibitory and cytotoxic effects of this compound. Normal prostate epithelial cells were generally less susceptible to the effects of belinostat than were prostate cancer cells. In an orthotopic prostate cancer tumor model, belinostat inhibited tumor growth by up to 43%. Moreover, metastatic lung lesions were present in 47% of vehicle‐treated animals but in none of the animals administered belinostat. Consistent with its observed antimetastatic activity, belinostat inhibited the migration of prostate tumor cells and increased the production of tissue inhibitor of metalloproteinase‐1 (TIMP‐1) by these cells, the latter effect being replicated by siRNA knockdown of HDAC3. Belinostat also increased the expression of p21 and decreased the expression of potentially oncogenic proteins (mutant p53 and ERG). These results support the clinical evaluation of belinostat for the treatment of prostate cancer. © 2007 Wiley‐Liss, Inc.