A novel mechanism of PPAR gamma induction via EGFR signalling constitutes rational for combination therapy in bladder cancer
Two signalling molecules that are attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor gamma (PPARγ). We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PP...
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| Veröffentlicht in: | PloS one 2013-02, Vol.8 (2), p.e55997 |
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| description | Two signalling molecules that are attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor gamma (PPARγ). We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PPARγ for anticancer therapy.
As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p |
| doi_str_mv | 10.1371/journal.pone.0055997 |
| format | Article |
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As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p<0.04). Induction of PPARγ expression along with nuclear accumulation was observed in response to increasing concentrations of gefitinib via activation of the transcription factor CCAT/enhancer-binding protein-β (CEBP-β). In these cell lines, DIM-C significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner.
These results suggest that PPARγ agonist DIM-C can be an excellent alternative to bladder tumors resistant to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0055997</identifier><identifier>PMID: 23409107</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiogenesis ; Animals ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacology ; Biology ; Biotechnology ; Bladder ; Bladder cancer ; Cancer ; Cancer therapies ; Cancer treatment ; CCAAT-Enhancer-Binding Protein-beta - genetics ; CCAAT-Enhancer-Binding Protein-beta - metabolism ; Cell cycle ; Cell growth ; Cell Line, Tumor ; Cell proliferation ; Combination therapy ; Comparative analysis ; Crosstalk ; Cyclin-dependent kinases ; Diabetes ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Therapy, Combination ; Epidermal growth factor ; Epidermal growth factor receptors ; Epidermal growth factors ; Female ; Gefitinib ; Gene Expression ; Gene Expression Regulation, Neoplastic - drug effects ; Health aspects ; Humans ; Immunoglobulins ; Inhibition ; Kinases ; Medicine ; Metastasis ; Mice ; Mutation ; Oncology ; Peroxisome proliferator-activated receptors ; PPAR gamma - agonists ; PPAR gamma - genetics ; PPAR gamma - metabolism ; Protein binding ; Protein Kinase Inhibitors - administration & dosage ; Protein Kinase Inhibitors - pharmacology ; PTEN Phosphohydrolase - genetics ; PTEN Phosphohydrolase - metabolism ; Quinazolines - administration & dosage ; Quinazolines - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - genetics ; Receptor, Epidermal Growth Factor - metabolism ; Rodents ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Therapy ; Transcription activation ; Tumor Burden - drug effects ; Tumor cell lines ; Tumors ; Urinary bladder ; Urinary Bladder Neoplasms - drug therapy ; Urinary Bladder Neoplasms - genetics ; Urinary Bladder Neoplasms - metabolism ; Urinary Bladder Neoplasms - pathology ; Urology ; Xenograft Model Antitumor Assays</subject><ispartof>PloS one, 2013-02, Vol.8 (2), p.e55997</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Mansure et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Mansure et al 2013 Mansure et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-64bcd52f87ee20bf126f8686274fc63763aa84043bcf6487471cd919b17ebeb53</citedby><cites>FETCH-LOGICAL-c692t-64bcd52f87ee20bf126f8686274fc63763aa84043bcf6487471cd919b17ebeb53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568080/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568080/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23409107$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ahmad, Aamir</contributor><creatorcontrib>Mansure, Jose Joao</creatorcontrib><creatorcontrib>Nassim, Roland</creatorcontrib><creatorcontrib>Chevalier, Simone</creatorcontrib><creatorcontrib>Szymanski, Konrad</creatorcontrib><creatorcontrib>Rocha, Joice</creatorcontrib><creatorcontrib>Aldousari, Saad</creatorcontrib><creatorcontrib>Kassouf, Wassim</creatorcontrib><title>A novel mechanism of PPAR gamma induction via EGFR signalling constitutes rational for combination therapy in bladder cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Two signalling molecules that are attractive for targeted therapy are the epidermal growth factor receptor (EGFR) and the peroxisome proliferator-activated receptor gamma (PPARγ). We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PPARγ for anticancer therapy.
As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p<0.04). Induction of PPARγ expression along with nuclear accumulation was observed in response to increasing concentrations of gefitinib via activation of the transcription factor CCAT/enhancer-binding protein-β (CEBP-β). In these cell lines, DIM-C significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner.
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drug effects</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immunoglobulins</subject><subject>Inhibition</subject><subject>Kinases</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>Mice</subject><subject>Mutation</subject><subject>Oncology</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>PPAR gamma - agonists</subject><subject>PPAR gamma - genetics</subject><subject>PPAR gamma - metabolism</subject><subject>Protein binding</subject><subject>Protein Kinase Inhibitors - administration & dosage</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>PTEN Phosphohydrolase - metabolism</subject><subject>Quinazolines - administration & dosage</subject><subject>Quinazolines - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Receptor, Epidermal Growth Factor - genetics</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Rodents</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Therapy</subject><subject>Transcription activation</subject><subject>Tumor Burden - drug effects</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Urinary bladder</subject><subject>Urinary Bladder Neoplasms - drug therapy</subject><subject>Urinary Bladder Neoplasms - genetics</subject><subject>Urinary Bladder Neoplasms - metabolism</subject><subject>Urinary Bladder Neoplasms - pathology</subject><subject>Urology</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</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><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl9r2zAUxc3YWLtu32BsgsFgD8lkS5bkl0EobRcotGR_XoUsS46CLaWSHFbYh5_SuCWGDYYfZO793aPL0cmytzmc54jmnzdu8FZ0862zag5hWVYVfZad5hUqZqSA6PnR_0n2KoRNghAj5GV2UiAMqxzS0-z3Ali3Ux3olVwLa0IPnAa3t4sVaEXfC2BsM8honAU7I8DF1eUKBNOmiztjWyCdDdHEIaoAvNhjogPa-dToa2MfKiCulRfb-yQF6k40jUptYaXyr7MXWnRBvRnPs-zH5cX386-z65ur5fnieiZJVcQZwbVsykIzqlQBa50XRDPCSEGxlgRRgoRgGGJUS00wo5jmsqnyqs6pqlVdorPs_UF327nAR-MCzxGCjDIGYSKWB6JxYsO33vTC33MnDH8oON9y4aORneJa4bqGdYWaimKFNWM6V5JQUWHCGlYlrS_jbUPdq0YqG73oJqLTjjVr3rodRyVhkO2X-TAKeHc3qBD_sfJItSJtZax2SUz2Jki-wJQhWiYnEjX_C5W-RvUmvZ7SJtUnA58mA4mJ6ldsxRACX35b_T9783PKfjxi10p0cR1cN-wTEqYgPoDSuxC80k_O5ZDvk__oBt8nn4_JT2Pvjl1_GnqMOvoDqCX_fg</recordid><startdate>20130208</startdate><enddate>20130208</enddate><creator>Mansure, Jose Joao</creator><creator>Nassim, Roland</creator><creator>Chevalier, Simone</creator><creator>Szymanski, Konrad</creator><creator>Rocha, Joice</creator><creator>Aldousari, Saad</creator><creator>Kassouf, Wassim</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130208</creationdate><title>A novel mechanism of PPAR gamma induction via EGFR signalling constitutes rational for combination therapy in bladder cancer</title><author>Mansure, Jose Joao ; Nassim, Roland ; Chevalier, Simone ; Szymanski, Konrad ; Rocha, Joice ; Aldousari, Saad ; Kassouf, Wassim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-64bcd52f87ee20bf126f8686274fc63763aa84043bcf6487471cd919b17ebeb53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biology</topic><topic>Biotechnology</topic><topic>Bladder</topic><topic>Bladder cancer</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cancer treatment</topic><topic>CCAAT-Enhancer-Binding Protein-beta - genetics</topic><topic>CCAAT-Enhancer-Binding Protein-beta - metabolism</topic><topic>Cell cycle</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Combination therapy</topic><topic>Comparative analysis</topic><topic>Crosstalk</topic><topic>Cyclin-dependent kinases</topic><topic>Diabetes</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Therapy, Combination</topic><topic>Epidermal growth factor</topic><topic>Epidermal growth factor receptors</topic><topic>Epidermal growth factors</topic><topic>Female</topic><topic>Gefitinib</topic><topic>Gene Expression</topic><topic>Gene Expression Regulation, Neoplastic - 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We investigated possible crosstalk between these 2 pathways, particularly in light of the recent evidence implicating PPARγ for anticancer therapy.
As evaluated by MTT assays, gefitinib (EGFR inhibitor) and DIM-C (PPARγ agonist) inhibited growth of 9 bladder cancer cell lines in a dose-dependent manner but with variable sensitivity. In addition, combination of gefitinib and DIM-C demonstrated maximal inhibition of cell proliferation compared to each drug alone. These findings were confirmed in vivo, where combination therapy maximally inhibited tumor growth in contrast to each treatment alone when compared to control (p<0.04). Induction of PPARγ expression along with nuclear accumulation was observed in response to increasing concentrations of gefitinib via activation of the transcription factor CCAT/enhancer-binding protein-β (CEBP-β). In these cell lines, DIM-C significantly sensitized bladder cancer cell lines that were resistant to EGFR inhibition in a schedule-specific manner.
These results suggest that PPARγ agonist DIM-C can be an excellent alternative to bladder tumors resistant to EGFR inhibition and combination efficacy might be achieved in a schedule-specific manner.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23409107</pmid><doi>10.1371/journal.pone.0055997</doi><tpages>e55997</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1330878800 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Angiogenesis Animals Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacology Biology Biotechnology Bladder Bladder cancer Cancer Cancer therapies Cancer treatment CCAAT-Enhancer-Binding Protein-beta - genetics CCAAT-Enhancer-Binding Protein-beta - metabolism Cell cycle Cell growth Cell Line, Tumor Cell proliferation Combination therapy Comparative analysis Crosstalk Cyclin-dependent kinases Diabetes Disease Models, Animal Dose-Response Relationship, Drug Drug Therapy, Combination Epidermal growth factor Epidermal growth factor receptors Epidermal growth factors Female Gefitinib Gene Expression Gene Expression Regulation, Neoplastic - drug effects Health aspects Humans Immunoglobulins Inhibition Kinases Medicine Metastasis Mice Mutation Oncology Peroxisome proliferator-activated receptors PPAR gamma - agonists PPAR gamma - genetics PPAR gamma - metabolism Protein binding Protein Kinase Inhibitors - administration & dosage Protein Kinase Inhibitors - pharmacology PTEN Phosphohydrolase - genetics PTEN Phosphohydrolase - metabolism Quinazolines - administration & dosage Quinazolines - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Rodents Signal transduction Signal Transduction - drug effects Signaling Therapy Transcription activation Tumor Burden - drug effects Tumor cell lines Tumors Urinary bladder Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - genetics Urinary Bladder Neoplasms - metabolism Urinary Bladder Neoplasms - pathology Urology Xenograft Model Antitumor Assays |
| title | A novel mechanism of PPAR gamma induction via EGFR signalling constitutes rational for combination therapy in bladder cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-05T02%3A56%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20novel%20mechanism%20of%20PPAR%20gamma%20induction%20via%20EGFR%20signalling%20constitutes%20rational%20for%20combination%20therapy%20in%20bladder%20cancer&rft.jtitle=PloS%20one&rft.au=Mansure,%20Jose%20Joao&rft.date=2013-02-08&rft.volume=8&rft.issue=2&rft.spage=e55997&rft.pages=e55997-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0055997&rft_dat=%3Cgale_plos_%3EA478375874%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1330878800&rft_id=info:pmid/23409107&rft_galeid=A478375874&rft_doaj_id=oai_doaj_org_article_fe4bb0b93d974e4f88f1ec67a9468d89&rfr_iscdi=true |