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The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer
Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene...
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| Published in: | Molecular cancer therapeutics 2009-08, Vol.8 (8), p.2221-2231 |
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| container_end_page | 2231 |
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| container_title | Molecular cancer therapeutics |
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| creator | Crisanti, M Cecilia Wallace, Africa F Kapoor, Veena Vandermeers, Fabian Dowling, Melissa L Pereira, Luana P Coleman, Kara Campling, Barbara G Fridlender, Zvi G Kao, Gary D Albelda, Steven M |
| description | Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase
inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and
nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival
pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat
was cytotoxic in almost all 37 cancer cell lines tested. IC 50 and LD 50 values were in the low nmol/L range (4–470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among
the most sensitive lines, with LD 50 values consistently |
| doi_str_mv | 10.1158/1535-7163.MCT-09-0138 |
| format | article |
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inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and
nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival
pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat
was cytotoxic in almost all 37 cancer cell lines tested. IC 50 and LD 50 values were in the low nmol/L range (4–470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among
the most sensitive lines, with LD 50 values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor
growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and
severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct
immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy
agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell
cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled
with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X L . These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially
SCLC. [Mol Cancer Ther 2009;8(8):2221–31]</description><identifier>ISSN: 1535-7163</identifier><identifier>ISSN: 1538-8514</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-09-0138</identifier><identifier>PMID: 19671764</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Carcinoma, Small Cell - drug therapy ; Carcinoma, Small Cell - enzymology ; Carcinoma, Small Cell - pathology ; Cell Line, Tumor ; etoposide and panobinostat ; Etoposide plus HDACi ; HDACi ; Histone Deacetylase Inhibitors - pharmacology ; Human health sciences ; Humans ; Hydroxamic Acids - pharmacology ; Indoles ; Lung Cancer ; Lung Neoplasms - drug therapy ; Lung Neoplasms - enzymology ; Lung Neoplasms - pathology ; Mesothelioma ; Mesothelioma - drug therapy ; Mesothelioma - pathology ; Oncologie ; Oncology ; Sciences de la santé humaine ; Small Cell Lung Cancer</subject><ispartof>Molecular cancer therapeutics, 2009-08, Vol.8 (8), p.2221-2231</ispartof><rights>Copyright © 2009 American Association for Cancer Research 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c490t-c6d362e6760ce31b9bb09d3d908683acc25635541a0d078d1b822db68ec5376d3</citedby><cites>FETCH-LOGICAL-c490t-c6d362e6760ce31b9bb09d3d908683acc25635541a0d078d1b822db68ec5376d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19671764$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Crisanti, M Cecilia</creatorcontrib><creatorcontrib>Wallace, Africa F</creatorcontrib><creatorcontrib>Kapoor, Veena</creatorcontrib><creatorcontrib>Vandermeers, Fabian</creatorcontrib><creatorcontrib>Dowling, Melissa L</creatorcontrib><creatorcontrib>Pereira, Luana P</creatorcontrib><creatorcontrib>Coleman, Kara</creatorcontrib><creatorcontrib>Campling, Barbara G</creatorcontrib><creatorcontrib>Fridlender, Zvi G</creatorcontrib><creatorcontrib>Kao, Gary D</creatorcontrib><creatorcontrib>Albelda, Steven M</creatorcontrib><title>The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase
inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and
nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival
pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat
was cytotoxic in almost all 37 cancer cell lines tested. IC 50 and LD 50 values were in the low nmol/L range (4–470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among
the most sensitive lines, with LD 50 values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor
growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and
severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct
immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy
agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell
cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled
with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X L . These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially
SCLC. [Mol Cancer Ther 2009;8(8):2221–31]</description><subject>Carcinoma, Small Cell - drug therapy</subject><subject>Carcinoma, Small Cell - enzymology</subject><subject>Carcinoma, Small Cell - pathology</subject><subject>Cell Line, Tumor</subject><subject>etoposide and panobinostat</subject><subject>Etoposide plus HDACi</subject><subject>HDACi</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Human health sciences</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Indoles</subject><subject>Lung Cancer</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - enzymology</subject><subject>Lung Neoplasms - pathology</subject><subject>Mesothelioma</subject><subject>Mesothelioma - drug therapy</subject><subject>Mesothelioma - pathology</subject><subject>Oncologie</subject><subject>Oncology</subject><subject>Sciences de la santé humaine</subject><subject>Small Cell Lung Cancer</subject><issn>1535-7163</issn><issn>1538-8514</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNpVUk2P0zAQjRCIXRZ-Asg34JDFH7VjX5CW8lGkIi7lbDnOJDFy4mInXe2P4b_ipoVdTh573nvzPDNF8ZLga0K4fEc442VFBLv-tt6VWJWYMPmouMzvspScrB4v8QlzUTxL6SfGRCpKnhYXRImKVGJ1Wfze9YA2H2_WyI29q90UItqbMdRuDGkyE3qz_bDhUr39m09ogBSmHrwLg0FmbJCfxw5ZM1qIyIL3KWPRwU0xLOnlcgjo1k191o6Ts7M3EUHbOmvsHWpzzTQY7xf2Q7nnxZPW-AQvzudV8ePzp916U26_f_m6vtmWdqXwVFrRMEFBVAJbYKRWdY1VwxqFpZDMWEu5YJyviMENrmRDaklpUwsJlrMqk6-K9yfd_VwP0FgYp2i83kc3mHing3H6_8zoet2Fg2YC5-bwLEBPAt5BBzrE2ukDXYhLPPtOG6tr0JQKqSXLvjPp9blqDL9mSJMeXDq2wIwQ5qQrxpSQVNGM5CekjSGlCO0_awTr4zro46j1cdQ6r4PGSh_XIfNePfzXPes8_3sLvev6WxdBnxofIYGJttfZa7ZMCfsDIafBCQ</recordid><startdate>20090801</startdate><enddate>20090801</enddate><creator>Crisanti, M Cecilia</creator><creator>Wallace, Africa F</creator><creator>Kapoor, Veena</creator><creator>Vandermeers, Fabian</creator><creator>Dowling, Melissa L</creator><creator>Pereira, Luana P</creator><creator>Coleman, Kara</creator><creator>Campling, Barbara G</creator><creator>Fridlender, Zvi G</creator><creator>Kao, Gary D</creator><creator>Albelda, Steven M</creator><general>American Association for Cancer Research</general><general>American Association for Cancer Research, Inc. 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Current therapies are inadequate. Histone deacetylase
inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and
nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival
pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat
was cytotoxic in almost all 37 cancer cell lines tested. IC 50 and LD 50 values were in the low nmol/L range (4–470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among
the most sensitive lines, with LD 50 values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor
growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and
severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct
immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy
agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell
cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled
with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X L . These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially
SCLC. [Mol Cancer Ther 2009;8(8):2221–31]</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>19671764</pmid><doi>10.1158/1535-7163.MCT-09-0138</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Carcinoma, Small Cell - drug therapy Carcinoma, Small Cell - enzymology Carcinoma, Small Cell - pathology Cell Line, Tumor etoposide and panobinostat Etoposide plus HDACi HDACi Histone Deacetylase Inhibitors - pharmacology Human health sciences Humans Hydroxamic Acids - pharmacology Indoles Lung Cancer Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - pathology Mesothelioma Mesothelioma - drug therapy Mesothelioma - pathology Oncologie Oncology Sciences de la santé humaine Small Cell Lung Cancer |
| title | The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer |
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