PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells
Proteasome inhibitor PS-341 (also known as bortezomib) and histone deacetylase (HDAC) inhibitors have emerged as novel therapeutic agents for a variety of malignancies. In this study, we examined whether PS-341 and the HDAC inhibitor trichostatin A (TSA) induced apoptosis in head and neck squamous c...
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| Veröffentlicht in: | Molecular cancer therapeutics 2010-07, Vol.9 (7), p.1977-1984 |
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| container_end_page | 1984 |
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| container_issue | 7 |
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| container_title | Molecular cancer therapeutics |
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| creator | Kim, Jinkoo Guan, Jean Chang, Insoon Chen, Xiaohong Han, Demin Wang, Cun-Yu |
| description | Proteasome inhibitor PS-341 (also known as bortezomib) and histone deacetylase (HDAC) inhibitors have emerged as novel therapeutic agents for a variety of malignancies. In this study, we examined whether PS-341 and the HDAC inhibitor trichostatin A (TSA) induced apoptosis in head and neck squamous cell carcinoma (HNSCC), a common and lethal malignancy. We found that, although TSA treatment alone did not induce apoptosis in HNSCC cells, it significantly enhanced PS-341-induced apoptosis in HNSCC cells in vitro. Consistently, TSA significantly improved PS-341-mediated inhibition of HNSCC tumor growth in nude mice. Mechanistically, we found that TSA increased PS-341-induced Noxa expression and caspase activation in HNSCC cells. The knockdown of Noxa significantly reduced apoptosis induced by cotreatment of PS-341 and TSA. Taken together, our results provide new insight into the mechanisms of synergistic antitumor activity of the PS-341 and HDAC inhibitor regimen, offering a new therapeutic strategy for HNSCC patients. |
| doi_str_mv | 10.1158/1535-7163.MCT-10-0141 |
| format | Article |
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In this study, we examined whether PS-341 and the HDAC inhibitor trichostatin A (TSA) induced apoptosis in head and neck squamous cell carcinoma (HNSCC), a common and lethal malignancy. We found that, although TSA treatment alone did not induce apoptosis in HNSCC cells, it significantly enhanced PS-341-induced apoptosis in HNSCC cells in vitro. Consistently, TSA significantly improved PS-341-mediated inhibition of HNSCC tumor growth in nude mice. Mechanistically, we found that TSA increased PS-341-induced Noxa expression and caspase activation in HNSCC cells. The knockdown of Noxa significantly reduced apoptosis induced by cotreatment of PS-341 and TSA. 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Taken together, our results provide new insight into the mechanisms of synergistic antitumor activity of the PS-341 and HDAC inhibitor regimen, offering a new therapeutic strategy for HNSCC patients.</description><subject>Acetylation - drug effects</subject><subject>Animals</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>Blotting, Northern</subject><subject>Blotting, Western</subject><subject>Boronic Acids - administration & dosage</subject><subject>Boronic Acids - pharmacology</subject><subject>Bortezomib</subject><subject>Carcinoma, Squamous Cell - drug therapy</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Carcinoma, Squamous Cell - pathology</subject><subject>Caspases - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Synergism</subject><subject>Enzyme Activation - drug effects</subject><subject>Head and Neck Neoplasms - drug therapy</subject><subject>Head and Neck Neoplasms - metabolism</subject><subject>Head and Neck Neoplasms - pathology</subject><subject>Histone Deacetylase Inhibitors - administration & dosage</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Hydroxamic Acids - administration & dosage</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Pyrazines - administration & dosage</subject><subject>Pyrazines - pharmacology</subject><subject>RNA Interference</subject><subject>Xenograft Model Antitumor Assays</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>eNpVkdtOwzAQRC0EoqXwCSD_QIo3zqV5QUIVN6kIJMqztXE2rSGNS5wg-vc4LVTwZHt2ZyydYewcxBggnlxCLOMghUSOH6fzAEQgIIIDNvT6JJjEEB1u77udATtx7k0ImGQhHLNBKOIURJIO2dfzSyAj4FgXfGlca2viBaGmdlOhI27qpclNaxvuNjU1C79iNFbVxk-KThPHtV231hnnBb4kLLZRNel37j46XNnOcU1VxTU22tR2hdunO2VHJVaOzn7OEXu9vZlP74PZ093D9HoW6AhEG4DMI62RMIMIwywNs7gQeYZCCsw0hkkKaZqXoghFSZnOPZucZIKpSEIqdSFH7GqXu-7yFRWa6rbBSq0bs8Jmoywa9X9Sm6Va2E8VZtITTXxAvAvQjXWuoXLvBaH6KlSPWfWYla-iV_sqvO_i78d71y97-Q2pR4jI</recordid><startdate>20100701</startdate><enddate>20100701</enddate><creator>Kim, Jinkoo</creator><creator>Guan, Jean</creator><creator>Chang, Insoon</creator><creator>Chen, Xiaohong</creator><creator>Han, Demin</creator><creator>Wang, Cun-Yu</creator><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>5PM</scope></search><sort><creationdate>20100701</creationdate><title>PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells</title><author>Kim, Jinkoo ; Guan, Jean ; Chang, Insoon ; Chen, Xiaohong ; Han, Demin ; Wang, Cun-Yu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-13b4ccaea914a297295d0b9a030a9ca267177bf0d20fe9cb115be36a7062efcd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Acetylation - drug effects</topic><topic>Animals</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Apoptosis - drug effects</topic><topic>Blotting, Northern</topic><topic>Blotting, Western</topic><topic>Boronic Acids - administration & dosage</topic><topic>Boronic Acids - pharmacology</topic><topic>Bortezomib</topic><topic>Carcinoma, Squamous Cell - drug therapy</topic><topic>Carcinoma, Squamous Cell - metabolism</topic><topic>Carcinoma, Squamous Cell - pathology</topic><topic>Caspases - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Synergism</topic><topic>Enzyme Activation - drug effects</topic><topic>Head and Neck Neoplasms - drug therapy</topic><topic>Head and Neck Neoplasms - metabolism</topic><topic>Head and Neck Neoplasms - pathology</topic><topic>Histone Deacetylase Inhibitors - administration & dosage</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Hydroxamic Acids - administration & dosage</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Pyrazines - administration & dosage</topic><topic>Pyrazines - pharmacology</topic><topic>RNA Interference</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Jinkoo</creatorcontrib><creatorcontrib>Guan, Jean</creatorcontrib><creatorcontrib>Chang, Insoon</creatorcontrib><creatorcontrib>Chen, Xiaohong</creatorcontrib><creatorcontrib>Han, Demin</creatorcontrib><creatorcontrib>Wang, Cun-Yu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Jinkoo</au><au>Guan, Jean</au><au>Chang, Insoon</au><au>Chen, Xiaohong</au><au>Han, Demin</au><au>Wang, Cun-Yu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2010-07-01</date><risdate>2010</risdate><volume>9</volume><issue>7</issue><spage>1977</spage><epage>1984</epage><pages>1977-1984</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Proteasome inhibitor PS-341 (also known as bortezomib) and histone deacetylase (HDAC) inhibitors have emerged as novel therapeutic agents for a variety of malignancies. In this study, we examined whether PS-341 and the HDAC inhibitor trichostatin A (TSA) induced apoptosis in head and neck squamous cell carcinoma (HNSCC), a common and lethal malignancy. We found that, although TSA treatment alone did not induce apoptosis in HNSCC cells, it significantly enhanced PS-341-induced apoptosis in HNSCC cells in vitro. Consistently, TSA significantly improved PS-341-mediated inhibition of HNSCC tumor growth in nude mice. Mechanistically, we found that TSA increased PS-341-induced Noxa expression and caspase activation in HNSCC cells. The knockdown of Noxa significantly reduced apoptosis induced by cotreatment of PS-341 and TSA. Taken together, our results provide new insight into the mechanisms of synergistic antitumor activity of the PS-341 and HDAC inhibitor regimen, offering a new therapeutic strategy for HNSCC patients.</abstract><cop>United States</cop><pmid>20571067</pmid><doi>10.1158/1535-7163.MCT-10-0141</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylation - drug effects Animals Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis - drug effects Blotting, Northern Blotting, Western Boronic Acids - administration & dosage Boronic Acids - pharmacology Bortezomib Carcinoma, Squamous Cell - drug therapy Carcinoma, Squamous Cell - metabolism Carcinoma, Squamous Cell - pathology Caspases - metabolism Cell Line, Tumor Dose-Response Relationship, Drug Drug Synergism Enzyme Activation - drug effects Head and Neck Neoplasms - drug therapy Head and Neck Neoplasms - metabolism Head and Neck Neoplasms - pathology Histone Deacetylase Inhibitors - administration & dosage Histone Deacetylase Inhibitors - pharmacology Histones - metabolism Humans Hydroxamic Acids - administration & dosage Hydroxamic Acids - pharmacology Mice Mice, Nude Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - metabolism Pyrazines - administration & dosage Pyrazines - pharmacology RNA Interference Xenograft Model Antitumor Assays |
| title | PS-341 and histone deacetylase inhibitor synergistically induce apoptosis in head and neck squamous cell carcinoma cells |
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