Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands
Evasion of death receptor ligand–induced apoptosis represents an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeu...
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| Veröffentlicht in: | Molecular cancer therapeutics 2010-01, Vol.9 (1), p.246-256 |
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| creator | Wood, Tabitha E Dalili, Shadi Simpson, Craig D Sukhai, Mahadeo A Hurren, Rose Anyiwe, Kika Mao, Xinliang Suarez Saiz, Fernando Gronda, Marcela Eberhard, Yanina MacLean, Neil Ketela, Troy Reed, John C Moffat, Jason Minden, Mark D Batey, Robert A Schimmer, Aaron D |
| description | Evasion of death receptor ligand–induced apoptosis represents an important contributor to cancer development and progression.
Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this
biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)- N -hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli,
decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better
understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands,
we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression
after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore,
we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and
that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have
identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby
highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246–56 |
| doi_str_mv | 10.1158/1535-7163.MCT-09-0495 |
| format | Article |
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Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this
biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)- N -hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli,
decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better
understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands,
we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression
after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore,
we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and
that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have
identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby
highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246–56</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-09-0495</identifier><identifier>PMID: 20053768</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Cell Line, Tumor ; death receptor pathway of caspase activation ; Drug Resistance, Neoplasm - drug effects ; Drug Screening Assays, Antitumor ; FAS ; fas Receptor - metabolism ; Gene Knockdown Techniques ; histone deacetylase ; Histone Deacetylase Inhibitors - chemistry ; Histone Deacetylase Inhibitors - pharmacology ; Histone Deacetylases - metabolism ; Humans ; Hydroxamic Acids - pharmacology ; Ligands ; Models, Molecular ; Neoplasms - enzymology ; Neoplasms - pathology ; Receptors, Death Domain - metabolism</subject><ispartof>Molecular cancer therapeutics, 2010-01, Vol.9 (1), p.246-256</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-797b6d858c8a812d5067ebd84f7f9ed6365cb3b50983af83b61d5cc6f54f3a9e3</citedby><cites>FETCH-LOGICAL-c504t-797b6d858c8a812d5067ebd84f7f9ed6365cb3b50983af83b61d5cc6f54f3a9e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20053768$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wood, Tabitha E</creatorcontrib><creatorcontrib>Dalili, Shadi</creatorcontrib><creatorcontrib>Simpson, Craig D</creatorcontrib><creatorcontrib>Sukhai, Mahadeo A</creatorcontrib><creatorcontrib>Hurren, Rose</creatorcontrib><creatorcontrib>Anyiwe, Kika</creatorcontrib><creatorcontrib>Mao, Xinliang</creatorcontrib><creatorcontrib>Suarez Saiz, Fernando</creatorcontrib><creatorcontrib>Gronda, Marcela</creatorcontrib><creatorcontrib>Eberhard, Yanina</creatorcontrib><creatorcontrib>MacLean, Neil</creatorcontrib><creatorcontrib>Ketela, Troy</creatorcontrib><creatorcontrib>Reed, John C</creatorcontrib><creatorcontrib>Moffat, Jason</creatorcontrib><creatorcontrib>Minden, Mark D</creatorcontrib><creatorcontrib>Batey, Robert A</creatorcontrib><creatorcontrib>Schimmer, Aaron D</creatorcontrib><title>Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Evasion of death receptor ligand–induced apoptosis represents an important contributor to cancer development and progression.
Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this
biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)- N -hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli,
decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better
understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands,
we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression
after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore,
we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and
that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have
identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby
highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246–56</description><subject>Cell Line, Tumor</subject><subject>death receptor pathway of caspase activation</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Screening Assays, Antitumor</subject><subject>FAS</subject><subject>fas Receptor - metabolism</subject><subject>Gene Knockdown Techniques</subject><subject>histone deacetylase</subject><subject>Histone Deacetylase Inhibitors - chemistry</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histone Deacetylases - metabolism</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Neoplasms - enzymology</subject><subject>Neoplasms - pathology</subject><subject>Receptors, Death Domain - metabolism</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMlOwzAQhi0EYik8AsgnOAXsOHbsIyqrVITEcrYcZ9IYpU6xXRA8PQktnObX6JtFH0LHlJxTyuUF5YxnJRXs_GH6khGVkULxLbQ_9GUmOS22f_Oa2UMHMb4RQqXK6S7aywnhrBRyH5ln6MAm9wH43reucsn1HvcNvnMx9R7wFRgL6aszESJ-Bh8H4nuID6Zzc298wlPouohTP6KpxU9gYZn6gGdubnwdD9FOY7oIR5s6Qa831y_Tu2z2eHs_vZxllpMiZaUqK1FLLq00kuY1J6KEqpZFUzYKasEEtxWrOFGSmUayStCaWysaXjTMKGATdLbeuwz9-wpi0gsX7fCb8dCvoi4ZE5TmjA4kX5M29DEGaPQyuIUJX5oSPcrVozg9itODXE2UHuUOcyebC6tqAfX_1J_NAThdA62bt58ugLbGWwgBIphgW6001Xkh2A8QyYQS</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>Wood, Tabitha E</creator><creator>Dalili, Shadi</creator><creator>Simpson, Craig D</creator><creator>Sukhai, Mahadeo A</creator><creator>Hurren, Rose</creator><creator>Anyiwe, Kika</creator><creator>Mao, Xinliang</creator><creator>Suarez Saiz, Fernando</creator><creator>Gronda, Marcela</creator><creator>Eberhard, Yanina</creator><creator>MacLean, Neil</creator><creator>Ketela, Troy</creator><creator>Reed, John C</creator><creator>Moffat, Jason</creator><creator>Minden, Mark D</creator><creator>Batey, Robert A</creator><creator>Schimmer, Aaron D</creator><general>American Association for Cancer Research</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20100101</creationdate><title>Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands</title><author>Wood, Tabitha E ; Dalili, Shadi ; Simpson, Craig D ; Sukhai, Mahadeo A ; Hurren, Rose ; Anyiwe, Kika ; Mao, Xinliang ; Suarez Saiz, Fernando ; Gronda, Marcela ; Eberhard, Yanina ; MacLean, Neil ; Ketela, Troy ; Reed, John C ; Moffat, Jason ; Minden, Mark D ; Batey, Robert A ; Schimmer, Aaron D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-797b6d858c8a812d5067ebd84f7f9ed6365cb3b50983af83b61d5cc6f54f3a9e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Cell Line, Tumor</topic><topic>death receptor pathway of caspase activation</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Screening Assays, Antitumor</topic><topic>FAS</topic><topic>fas Receptor - metabolism</topic><topic>Gene Knockdown Techniques</topic><topic>histone deacetylase</topic><topic>Histone Deacetylase Inhibitors - chemistry</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histone Deacetylases - metabolism</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Neoplasms - enzymology</topic><topic>Neoplasms - pathology</topic><topic>Receptors, Death Domain - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wood, Tabitha E</creatorcontrib><creatorcontrib>Dalili, Shadi</creatorcontrib><creatorcontrib>Simpson, Craig D</creatorcontrib><creatorcontrib>Sukhai, Mahadeo A</creatorcontrib><creatorcontrib>Hurren, Rose</creatorcontrib><creatorcontrib>Anyiwe, Kika</creatorcontrib><creatorcontrib>Mao, Xinliang</creatorcontrib><creatorcontrib>Suarez Saiz, Fernando</creatorcontrib><creatorcontrib>Gronda, Marcela</creatorcontrib><creatorcontrib>Eberhard, Yanina</creatorcontrib><creatorcontrib>MacLean, Neil</creatorcontrib><creatorcontrib>Ketela, Troy</creatorcontrib><creatorcontrib>Reed, John C</creatorcontrib><creatorcontrib>Moffat, Jason</creatorcontrib><creatorcontrib>Minden, Mark D</creatorcontrib><creatorcontrib>Batey, Robert A</creatorcontrib><creatorcontrib>Schimmer, Aaron D</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wood, Tabitha E</au><au>Dalili, Shadi</au><au>Simpson, Craig D</au><au>Sukhai, Mahadeo A</au><au>Hurren, Rose</au><au>Anyiwe, Kika</au><au>Mao, Xinliang</au><au>Suarez Saiz, Fernando</au><au>Gronda, Marcela</au><au>Eberhard, Yanina</au><au>MacLean, Neil</au><au>Ketela, Troy</au><au>Reed, John C</au><au>Moffat, Jason</au><au>Minden, Mark D</au><au>Batey, Robert A</au><au>Schimmer, Aaron D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>9</volume><issue>1</issue><spage>246</spage><epage>256</epage><pages>246-256</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Evasion of death receptor ligand–induced apoptosis represents an important contributor to cancer development and progression.
Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this
biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule 4-(4-chloro-2-methylphenoxy)- N -hydroxybutanamide (that we propose be named droxinostat) was identified as a chemical sensitizer to death receptor stimuli,
decreasing the expression of the caspase-8 inhibitor FLIP. However, the direct targets of droxinostat were unknown. To better
understand the mechanism of action of droxinostat and highlight new strategies to restore sensitivity to death receptor ligands,
we analyzed changes in gene expression using the Connectivity Map after treating cells with droxinostat. Changes in gene expression
after droxinostat treatment resembled changes observed after treatment with histone deacetylase (HDAC) inhibitors. Therefore,
we examined the effects of droxinostat on HDAC activity and showed that it selectively inhibited HDAC3, HDAC6, and HDAC8 and
that inhibition of these HDACs was functionally important for its ability to sensitize cells to death ligands. Thus, we have
identified a selective HDAC inhibitor and showed that selective HDAC inhibition sensitizes cells to death ligands, thereby
highlighting a new mechanism to overcome resistance to death receptor ligands. Mol Cancer Ther; 9(1); 246–56</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>20053768</pmid><doi>10.1158/1535-7163.MCT-09-0495</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1535-7163 |
| ispartof | Molecular cancer therapeutics, 2010-01, Vol.9 (1), p.246-256 |
| issn | 1535-7163 1538-8514 |
| language | eng |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Cell Line, Tumor death receptor pathway of caspase activation Drug Resistance, Neoplasm - drug effects Drug Screening Assays, Antitumor FAS fas Receptor - metabolism Gene Knockdown Techniques histone deacetylase Histone Deacetylase Inhibitors - chemistry Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - metabolism Humans Hydroxamic Acids - pharmacology Ligands Models, Molecular Neoplasms - enzymology Neoplasms - pathology Receptors, Death Domain - metabolism |
| title | Selective Inhibition of Histone Deacetylases Sensitizes Malignant Cells to Death Receptor Ligands |
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