Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists
The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure...
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| Veröffentlicht in: | Investigational new drugs 2005-10, Vol.23 (5), p.417-428 |
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| creator | Benbrook, Doris M Kamelle, Scott A Guruswamy, Suresh B Lightfoot, Stan A Rutledge, Teresa L Gould, Natalie S Hannafon, Bethany N Dunn, S Terence Berlin, K Darrell |
| description | The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists. |
| doi_str_mv | 10.1007/s10637-005-2901-5 |
| format | Article |
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Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.</description><identifier>ISSN: 0167-6997</identifier><identifier>EISSN: 1573-0646</identifier><identifier>DOI: 10.1007/s10637-005-2901-5</identifier><identifier>PMID: 16133793</identifier><identifier>CODEN: INNDDK</identifier><language>eng</language><publisher>United States: Springer Nature B.V</publisher><subject>Acids ; Alanine Transaminase - blood ; Animals ; Antibiotics ; Antineoplastic Agents - pharmacology ; Apoptosis ; Cancer therapies ; Cell cycle ; Cell Differentiation - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chromans - pharmacology ; Drug dosages ; Female ; Gene Expression Regulation, Neoplastic - drug effects ; Head & neck cancer ; Health sciences ; Humans ; Mice ; Mice, Inbred Strains ; Ovarian cancer ; Ovarian Neoplasms - drug therapy ; Phenylurea Compounds - pharmacology ; Ratios ; Receptors, Retinoic Acid - agonists ; Receptors, Retinoic Acid - genetics ; Receptors, Retinoic Acid - metabolism ; Retinoid X Receptors - agonists ; Retinoid X Receptors - genetics ; Retinoid X Receptors - metabolism ; RNA - metabolism ; Skin Irritancy Tests ; Thiones - pharmacology ; Thiourea - analogs & derivatives ; Thiourea - pharmacology ; Toxicity ; Transcription factors ; Uterine Cervical Neoplasms - drug therapy ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - metabolism ; Xenograft Model Antitumor Assays</subject><ispartof>Investigational new drugs, 2005-10, Vol.23 (5), p.417-428</ispartof><rights>Springer Science + Business Media, Inc. 2005</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c357t-b258712a120bc0463cf74f8a67ec5162ecf844d63fd455764788c0b10d5e9ed23</citedby><cites>FETCH-LOGICAL-c357t-b258712a120bc0463cf74f8a67ec5162ecf844d63fd455764788c0b10d5e9ed23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16133793$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Benbrook, Doris M</creatorcontrib><creatorcontrib>Kamelle, Scott A</creatorcontrib><creatorcontrib>Guruswamy, Suresh B</creatorcontrib><creatorcontrib>Lightfoot, Stan A</creatorcontrib><creatorcontrib>Rutledge, Teresa L</creatorcontrib><creatorcontrib>Gould, Natalie S</creatorcontrib><creatorcontrib>Hannafon, Bethany N</creatorcontrib><creatorcontrib>Dunn, S Terence</creatorcontrib><creatorcontrib>Berlin, K Darrell</creatorcontrib><title>Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists</title><title>Investigational new drugs</title><addtitle>Invest New Drugs</addtitle><description>The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.</description><subject>Acids</subject><subject>Alanine Transaminase - blood</subject><subject>Animals</subject><subject>Antibiotics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chromans - pharmacology</subject><subject>Drug dosages</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Head & neck cancer</subject><subject>Health sciences</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Ratios</subject><subject>Receptors, Retinoic Acid - agonists</subject><subject>Receptors, Retinoic Acid - genetics</subject><subject>Receptors, Retinoic Acid - metabolism</subject><subject>Retinoid X Receptors - agonists</subject><subject>Retinoid X Receptors - genetics</subject><subject>Retinoid X Receptors - metabolism</subject><subject>RNA - metabolism</subject><subject>Skin Irritancy Tests</subject><subject>Thiones - pharmacology</subject><subject>Thiourea - analogs & derivatives</subject><subject>Thiourea - pharmacology</subject><subject>Toxicity</subject><subject>Transcription factors</subject><subject>Uterine Cervical Neoplasms - drug therapy</subject><subject>Uterine Cervical Neoplasms - genetics</subject><subject>Uterine Cervical Neoplasms - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0167-6997</issn><issn>1573-0646</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><recordid>eNpdkU1r3DAQhkVJabZpf0AvReQQ2oPSkfVlH0NomkKgl-YsZHncVfBaG0ku6T0_vHJ3IVAQDGKeeZnhIeQDh0sOYL5kDloYBqBY0wFn6hXZcGUEAy31CdkA14bprjOn5G3ODwAgOiPfkFOuuRCmExvyfDPhU-gnpFssmKJLsYQ5hiHTT2uL3WLJnyk-bUMfCg27fYq_caBli8ntcSnB0-RKiJm6-uYSmHezx0TdL5xLppVONOG_UE-dD0P9edyXuCJxDrnkd-T16KaM74_1jNzffP15fcvufnz7fn11x7xQprC-Ua3hjeMN9B6kFn40cmydNugV1w36sZVy0GIcpFJGS9O2HnoOg8IOh0ackYtDbj3iccFc7C5kj9PkZoxLtg20uuG6reD5f-BDXNJcd7O1Lztt2jWNHyCfYs4JR7tPYefSH8vBrn7swY-tfuzqx6o68_EYvPQ7HF4mjkLEXyNfjRU</recordid><startdate>200510</startdate><enddate>200510</enddate><creator>Benbrook, Doris M</creator><creator>Kamelle, Scott A</creator><creator>Guruswamy, Suresh B</creator><creator>Lightfoot, Stan A</creator><creator>Rutledge, Teresa L</creator><creator>Gould, Natalie S</creator><creator>Hannafon, Bethany N</creator><creator>Dunn, S Terence</creator><creator>Berlin, K Darrell</creator><general>Springer Nature B.V</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>3V.</scope><scope>7QO</scope><scope>7RV</scope><scope>7WY</scope><scope>7WZ</scope><scope>7X7</scope><scope>7XB</scope><scope>87Z</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8FL</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BEZIV</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FRNLG</scope><scope>FYUFA</scope><scope>F~G</scope><scope>GHDGH</scope><scope>K60</scope><scope>K6~</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>L.-</scope><scope>M0C</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PQBIZ</scope><scope>PQBZA</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope></search><sort><creationdate>200510</creationdate><title>Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists</title><author>Benbrook, Doris M ; Kamelle, Scott A ; Guruswamy, Suresh B ; Lightfoot, Stan A ; Rutledge, Teresa L ; Gould, Natalie S ; Hannafon, Bethany N ; Dunn, S Terence ; Berlin, K Darrell</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c357t-b258712a120bc0463cf74f8a67ec5162ecf844d63fd455764788c0b10d5e9ed23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Acids</topic><topic>Alanine Transaminase - 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metabolism</topic><topic>RNA - metabolism</topic><topic>Skin Irritancy Tests</topic><topic>Thiones - pharmacology</topic><topic>Thiourea - analogs & derivatives</topic><topic>Thiourea - pharmacology</topic><topic>Toxicity</topic><topic>Transcription factors</topic><topic>Uterine Cervical Neoplasms - drug therapy</topic><topic>Uterine Cervical Neoplasms - genetics</topic><topic>Uterine Cervical Neoplasms - metabolism</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Benbrook, Doris M</creatorcontrib><creatorcontrib>Kamelle, Scott A</creatorcontrib><creatorcontrib>Guruswamy, Suresh B</creatorcontrib><creatorcontrib>Lightfoot, Stan A</creatorcontrib><creatorcontrib>Rutledge, Teresa L</creatorcontrib><creatorcontrib>Gould, Natalie S</creatorcontrib><creatorcontrib>Hannafon, Bethany N</creatorcontrib><creatorcontrib>Dunn, S Terence</creatorcontrib><creatorcontrib>Berlin, K Darrell</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Access via ABI/INFORM (ProQuest)</collection><collection>ABI/INFORM Global (PDF only)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ABI/INFORM Global (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ABI/INFORM Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>Business Premium Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Business Premium Collection (Alumni)</collection><collection>Health Research Premium Collection</collection><collection>ABI/INFORM Global (Corporate)</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Business Collection (Alumni Edition)</collection><collection>ProQuest Business Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ABI/INFORM Professional Advanced</collection><collection>ABI/INFORM Global</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Business</collection><collection>ProQuest One Business (Alumni)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><jtitle>Investigational new drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Benbrook, Doris M</au><au>Kamelle, Scott A</au><au>Guruswamy, Suresh B</au><au>Lightfoot, Stan A</au><au>Rutledge, Teresa L</au><au>Gould, Natalie S</au><au>Hannafon, Bethany N</au><au>Dunn, S Terence</au><au>Berlin, K Darrell</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists</atitle><jtitle>Investigational new drugs</jtitle><addtitle>Invest New Drugs</addtitle><date>2005-10</date><risdate>2005</risdate><volume>23</volume><issue>5</issue><spage>417</spage><epage>428</epage><pages>417-428</pages><issn>0167-6997</issn><eissn>1573-0646</eissn><coden>INNDDK</coden><abstract>The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic retinoids are mediated through nuclear RA receptors (RARs) and retinoid X receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit similar anti-cancer activities, but reduced toxicity in vivo, in comparison to parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 3-atom urea or thiourea linkers, regulate growth and differentiation similar to RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent apoptosis in ovarian cancer and in head and neck cancer cell lines through the intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were growth inhibited by micromolar concentrations of Flex-Hets to greater extents than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each cell line of the National Cancer Institute's human tumor cell line panel at micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. None of these compounds induced evidence of skin, bone or liver toxicity, or increased levels of serum alanine aminotransferase (ALT) in the treated mice. Topical application of Flex-Hets did not induce skin irritation in vivo, whereas a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic ratios for multiple cancer types over RAR and/or RXR agonists.</abstract><cop>United States</cop><pub>Springer Nature B.V</pub><pmid>16133793</pmid><doi>10.1007/s10637-005-2901-5</doi><tpages>12</tpages></addata></record> |
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| subjects | Acids Alanine Transaminase - blood Animals Antibiotics Antineoplastic Agents - pharmacology Apoptosis Cancer therapies Cell cycle Cell Differentiation - drug effects Cell Line, Tumor Cell Proliferation - drug effects Chromans - pharmacology Drug dosages Female Gene Expression Regulation, Neoplastic - drug effects Head & neck cancer Health sciences Humans Mice Mice, Inbred Strains Ovarian cancer Ovarian Neoplasms - drug therapy Phenylurea Compounds - pharmacology Ratios Receptors, Retinoic Acid - agonists Receptors, Retinoic Acid - genetics Receptors, Retinoic Acid - metabolism Retinoid X Receptors - agonists Retinoid X Receptors - genetics Retinoid X Receptors - metabolism RNA - metabolism Skin Irritancy Tests Thiones - pharmacology Thiourea - analogs & derivatives Thiourea - pharmacology Toxicity Transcription factors Uterine Cervical Neoplasms - drug therapy Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - metabolism Xenograft Model Antitumor Assays |
| title | Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as anti-cancer agents over retinoic acid receptor agonists |
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