Abstract:
:Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Feng R,Ma H,Hassig CA,Payne JE,Smith ND,Mapara MY,Hager JH,Lentzsch Sdoi
10.1158/1535-7163.MCT-08-0183subject
Has Abstractpub_date
2008-06-01 00:00:00pages
1494-505issue
6eissn
1535-7163issn
1538-8514pii
7/6/1494journal_volume
7pub_type
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pub_type: 杂志文章
doi:
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pub_type: 杂志文章
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更新日期:2005-07-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0237
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-1097
更新日期:2009-05-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2004-12-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-08-01 00:00:00
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pub_type: 杂志文章
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更新日期:2004-06-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,多中心研究
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更新日期:2016-03-01 00:00:00
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更新日期:2005-11-01 00:00:00
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-04-0290
更新日期:2005-04-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0079
更新日期:2007-10-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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更新日期:2012-03-01 00:00:00
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pub_type: 杂志文章
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更新日期:2010-12-01 00:00:00