P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines
Development of new molecular target therapeutic agents is expected to improve clinical outcome, ideally with efficacy in both single and combined treatment modalities. Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp...
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| Veröffentlicht in: | International journal of oncology 2006-11, Vol.29 (5), p.1111-1117 |
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| creator | SHINTANI, S ZHANG, T ASLAM, A SEBASTIAN, K YOSHIMURA, T HAMAKAWA, H |
| description | Development of new molecular target therapeutic agents is expected to improve clinical outcome, ideally with efficacy in both single and combined treatment modalities. Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp90) may provide a strategy for enhancing tumor cell radiation sensitivity. Therefore, we have investigated the effects of Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on radiation sensitivity of human tumor cells in vitro. We evaluated the effects of 17-AAG using oral squamous cell carcinoma (OSCC) cell lines (HSC2, HSC3 and HSC4), including two types of SAS cells with a wild-type (SAS/neo), or a mutated p53 status (SAS/Trp248). Apoptosis and clonogenic survival were examined after exposure of the cells to radiation. For mechanistic insight, we analyzed cell cycle, several signaling factors and molecular markers including Akt, Raf-1, p38 MAPK, Cdc25B, Cdc25C, Cdk2 and p21. Treatment of OSCC cell lines with 17-AAG resulted in cytotoxicity and, when combined with radiation, enhanced the radiation response. However, the responses depended on p53 status. 17-AAG enhanced the radiation sensitivity significantly and induced apoptosis in the SAS/neo cell which has a wild-type p53. But the radiation sensitizing effect of 17-AAG was limited in the SAS/Trp248 cell which has a mutated p53. We also measured the total levels of several prosurvival and cell cycle signaling proteins. Akt, Raf-1 and Cdc25C expression were down-regulated in 17-AAG-treated cells. These data indicate that 17-AAG inhibits the proliferation and enhances the radiation sensitivity of human OSCC cells in various levels. However, enhancement of radiation sensitivity by the Hsp90 inhibitor depended on p53 status. Therefore, Hsp90 therapy combined with radiation might synergize with conventional therapies in patients with wild-type p53. |
| doi_str_mv | 10.3892/ijo.29.5.1111 |
| format | Article |
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Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp90) may provide a strategy for enhancing tumor cell radiation sensitivity. Therefore, we have investigated the effects of Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on radiation sensitivity of human tumor cells in vitro. We evaluated the effects of 17-AAG using oral squamous cell carcinoma (OSCC) cell lines (HSC2, HSC3 and HSC4), including two types of SAS cells with a wild-type (SAS/neo), or a mutated p53 status (SAS/Trp248). Apoptosis and clonogenic survival were examined after exposure of the cells to radiation. For mechanistic insight, we analyzed cell cycle, several signaling factors and molecular markers including Akt, Raf-1, p38 MAPK, Cdc25B, Cdc25C, Cdk2 and p21. Treatment of OSCC cell lines with 17-AAG resulted in cytotoxicity and, when combined with radiation, enhanced the radiation response. However, the responses depended on p53 status. 17-AAG enhanced the radiation sensitivity significantly and induced apoptosis in the SAS/neo cell which has a wild-type p53. But the radiation sensitizing effect of 17-AAG was limited in the SAS/Trp248 cell which has a mutated p53. We also measured the total levels of several prosurvival and cell cycle signaling proteins. Akt, Raf-1 and Cdc25C expression were down-regulated in 17-AAG-treated cells. These data indicate that 17-AAG inhibits the proliferation and enhances the radiation sensitivity of human OSCC cells in various levels. However, enhancement of radiation sensitivity by the Hsp90 inhibitor depended on p53 status. Therefore, Hsp90 therapy combined with radiation might synergize with conventional therapies in patients with wild-type p53.</description><identifier>ISSN: 1019-6439</identifier><identifier>EISSN: 1791-2423</identifier><identifier>DOI: 10.3892/ijo.29.5.1111</identifier><identifier>PMID: 17016641</identifier><language>eng</language><publisher>Athens: Editorial Academy of the International Journal of Oncology</publisher><subject>Apoptosis ; Benzoquinones - pharmacology ; Biological and medical sciences ; Carcinoma, Squamous Cell - chemistry ; Carcinoma, Squamous Cell - radiotherapy ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Proliferation - radiation effects ; HSP90 Heat-Shock Proteins - analysis ; HSP90 Heat-Shock Proteins - antagonists & inhibitors ; HSP90 Heat-Shock Proteins - metabolism ; Humans ; Lactams, Macrocyclic - pharmacology ; Medical sciences ; Mouth Neoplasms - chemistry ; Mouth Neoplasms - radiotherapy ; Otorhinolaryngology. Stomatology ; Radiation Tolerance - drug effects ; Radiation Tolerance - genetics ; Tumor Suppressor Protein p53 - genetics ; Tumors ; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology</subject><ispartof>International journal of oncology, 2006-11, Vol.29 (5), p.1111-1117</ispartof><rights>2006 INIST-CNRS</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c457t-36f555ac4629da51c2fd3065329f65cc143ab3db9b015ab2154ee02c937abd243</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18225321$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17016641$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SHINTANI, S</creatorcontrib><creatorcontrib>ZHANG, T</creatorcontrib><creatorcontrib>ASLAM, A</creatorcontrib><creatorcontrib>SEBASTIAN, K</creatorcontrib><creatorcontrib>YOSHIMURA, T</creatorcontrib><creatorcontrib>HAMAKAWA, H</creatorcontrib><title>P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines</title><title>International journal of oncology</title><addtitle>Int J Oncol</addtitle><description>Development of new molecular target therapeutic agents is expected to improve clinical outcome, ideally with efficacy in both single and combined treatment modalities. Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp90) may provide a strategy for enhancing tumor cell radiation sensitivity. Therefore, we have investigated the effects of Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on radiation sensitivity of human tumor cells in vitro. We evaluated the effects of 17-AAG using oral squamous cell carcinoma (OSCC) cell lines (HSC2, HSC3 and HSC4), including two types of SAS cells with a wild-type (SAS/neo), or a mutated p53 status (SAS/Trp248). Apoptosis and clonogenic survival were examined after exposure of the cells to radiation. For mechanistic insight, we analyzed cell cycle, several signaling factors and molecular markers including Akt, Raf-1, p38 MAPK, Cdc25B, Cdc25C, Cdk2 and p21. Treatment of OSCC cell lines with 17-AAG resulted in cytotoxicity and, when combined with radiation, enhanced the radiation response. However, the responses depended on p53 status. 17-AAG enhanced the radiation sensitivity significantly and induced apoptosis in the SAS/neo cell which has a wild-type p53. But the radiation sensitizing effect of 17-AAG was limited in the SAS/Trp248 cell which has a mutated p53. We also measured the total levels of several prosurvival and cell cycle signaling proteins. Akt, Raf-1 and Cdc25C expression were down-regulated in 17-AAG-treated cells. These data indicate that 17-AAG inhibits the proliferation and enhances the radiation sensitivity of human OSCC cells in various levels. However, enhancement of radiation sensitivity by the Hsp90 inhibitor depended on p53 status. Therefore, Hsp90 therapy combined with radiation might synergize with conventional therapies in patients with wild-type p53.</description><subject>Apoptosis</subject><subject>Benzoquinones - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Carcinoma, Squamous Cell - chemistry</subject><subject>Carcinoma, Squamous Cell - radiotherapy</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - radiation effects</subject><subject>HSP90 Heat-Shock Proteins - analysis</subject><subject>HSP90 Heat-Shock Proteins - antagonists & inhibitors</subject><subject>HSP90 Heat-Shock Proteins - metabolism</subject><subject>Humans</subject><subject>Lactams, Macrocyclic - pharmacology</subject><subject>Medical sciences</subject><subject>Mouth Neoplasms - chemistry</subject><subject>Mouth Neoplasms - radiotherapy</subject><subject>Otorhinolaryngology. Stomatology</subject><subject>Radiation Tolerance - drug effects</subject><subject>Radiation Tolerance - genetics</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumors</subject><subject>Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology</subject><issn>1019-6439</issn><issn>1791-2423</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0T1rHDEQBuAlJMSOkzJtUBN3e9b3rspgEttgcIqkFrP68MlopbO0C7n8C__j6LgDl1GjGXgYZni77jPBGzYqehWe8oaqjdiQ9t5052RQpKecsretxkT1kjN11n2o9QljKgQm77szMmAiJSfn3ctPwXrrdi5ZlxZUwIZcXaphCX9DekTOe2eWirJHt3WnMAppG6aw5ILI0EOM-whzSLlvnXWzW7b5z_7RRQsJ5r0JCeWEtusMrSgQUX1eYc5rRcbFiAyURvIMxzaG5OrH7p2HWN2n03_R_f7x_df1bX__cHN3_e2-N1wMS8-kF0KA4ZIqC4IY6i3DUjCqvBTGEM5gYnZSEyYCJkoEdw5To9gAk6WcXXSXx7m7kp9XVxc9h3pYA5JrC2o5KiL5KP4LiZKKUjw22B-hKbnW4rzelTBD2WuC9SEs3cLSVGmhD2E1_-U0eJ1mZ1_1KZ0Gvp4AVAPRF0gm1Fc3UtruJewfsoOe3A</recordid><startdate>20061101</startdate><enddate>20061101</enddate><creator>SHINTANI, S</creator><creator>ZHANG, T</creator><creator>ASLAM, A</creator><creator>SEBASTIAN, K</creator><creator>YOSHIMURA, T</creator><creator>HAMAKAWA, H</creator><general>Editorial Academy of the International Journal of Oncology</general><scope>IQODW</scope><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>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20061101</creationdate><title>P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines</title><author>SHINTANI, S ; ZHANG, T ; ASLAM, A ; SEBASTIAN, K ; YOSHIMURA, T ; HAMAKAWA, H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c457t-36f555ac4629da51c2fd3065329f65cc143ab3db9b015ab2154ee02c937abd243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Apoptosis</topic><topic>Benzoquinones - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Carcinoma, Squamous Cell - chemistry</topic><topic>Carcinoma, Squamous Cell - radiotherapy</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Proliferation - radiation effects</topic><topic>HSP90 Heat-Shock Proteins - analysis</topic><topic>HSP90 Heat-Shock Proteins - antagonists & inhibitors</topic><topic>HSP90 Heat-Shock Proteins - metabolism</topic><topic>Humans</topic><topic>Lactams, Macrocyclic - pharmacology</topic><topic>Medical sciences</topic><topic>Mouth Neoplasms - chemistry</topic><topic>Mouth Neoplasms - radiotherapy</topic><topic>Otorhinolaryngology. Stomatology</topic><topic>Radiation Tolerance - drug effects</topic><topic>Radiation Tolerance - genetics</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumors</topic><topic>Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology</topic><toplevel>online_resources</toplevel><creatorcontrib>SHINTANI, S</creatorcontrib><creatorcontrib>ZHANG, T</creatorcontrib><creatorcontrib>ASLAM, A</creatorcontrib><creatorcontrib>SEBASTIAN, K</creatorcontrib><creatorcontrib>YOSHIMURA, T</creatorcontrib><creatorcontrib>HAMAKAWA, H</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SHINTANI, S</au><au>ZHANG, T</au><au>ASLAM, A</au><au>SEBASTIAN, K</au><au>YOSHIMURA, T</au><au>HAMAKAWA, H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines</atitle><jtitle>International journal of oncology</jtitle><addtitle>Int J Oncol</addtitle><date>2006-11-01</date><risdate>2006</risdate><volume>29</volume><issue>5</issue><spage>1111</spage><epage>1117</epage><pages>1111-1117</pages><issn>1019-6439</issn><eissn>1791-2423</eissn><abstract>Development of new molecular target therapeutic agents is expected to improve clinical outcome, ideally with efficacy in both single and combined treatment modalities. Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp90) may provide a strategy for enhancing tumor cell radiation sensitivity. Therefore, we have investigated the effects of Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on radiation sensitivity of human tumor cells in vitro. We evaluated the effects of 17-AAG using oral squamous cell carcinoma (OSCC) cell lines (HSC2, HSC3 and HSC4), including two types of SAS cells with a wild-type (SAS/neo), or a mutated p53 status (SAS/Trp248). Apoptosis and clonogenic survival were examined after exposure of the cells to radiation. For mechanistic insight, we analyzed cell cycle, several signaling factors and molecular markers including Akt, Raf-1, p38 MAPK, Cdc25B, Cdc25C, Cdk2 and p21. Treatment of OSCC cell lines with 17-AAG resulted in cytotoxicity and, when combined with radiation, enhanced the radiation response. However, the responses depended on p53 status. 17-AAG enhanced the radiation sensitivity significantly and induced apoptosis in the SAS/neo cell which has a wild-type p53. But the radiation sensitizing effect of 17-AAG was limited in the SAS/Trp248 cell which has a mutated p53. We also measured the total levels of several prosurvival and cell cycle signaling proteins. Akt, Raf-1 and Cdc25C expression were down-regulated in 17-AAG-treated cells. These data indicate that 17-AAG inhibits the proliferation and enhances the radiation sensitivity of human OSCC cells in various levels. However, enhancement of radiation sensitivity by the Hsp90 inhibitor depended on p53 status. Therefore, Hsp90 therapy combined with radiation might synergize with conventional therapies in patients with wild-type p53.</abstract><cop>Athens</cop><pub>Editorial Academy of the International Journal of Oncology</pub><pmid>17016641</pmid><doi>10.3892/ijo.29.5.1111</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| source | Spandidos Publications Journals; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Apoptosis Benzoquinones - pharmacology Biological and medical sciences Carcinoma, Squamous Cell - chemistry Carcinoma, Squamous Cell - radiotherapy Cell Line, Tumor Cell Proliferation - drug effects Cell Proliferation - radiation effects HSP90 Heat-Shock Proteins - analysis HSP90 Heat-Shock Proteins - antagonists & inhibitors HSP90 Heat-Shock Proteins - metabolism Humans Lactams, Macrocyclic - pharmacology Medical sciences Mouth Neoplasms - chemistry Mouth Neoplasms - radiotherapy Otorhinolaryngology. Stomatology Radiation Tolerance - drug effects Radiation Tolerance - genetics Tumor Suppressor Protein p53 - genetics Tumors Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology |
| title | P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines |
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