Targeting apoptosis pathways in pancreatic cancer
Pancreatic cancer – here in particular pancreatic ductal adenocarcinoma (PDAC) – is still a highly therapy refractory disease. Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resis...
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Veröffentlicht in: | Cancer letters 2013-05, Vol.332 (2), p.346-358 |
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description | Pancreatic cancer – here in particular pancreatic ductal adenocarcinoma (PDAC) – is still a highly therapy refractory disease. Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resistance to apoptotic stimuli such as death ligands (FasL, TRAIL) or anti-cancer drugs (gemcitabine) by a great number of molecular alterations either disrupting an apoptosis inducing signal or counteracting the execution of apoptosis. Thus, PDAC cells exhibit alterations in the EGFR/MAPK/Ras/raf1-, PI3K/Akt-, TRAIL/TRAF2-, or IKK/NF-κB pathway accompanied by deregulations in the expression of apoptosis regulators such as cIAP, Bcl2, XIAP or survivin. Along with protection against apoptosis, PDAC cells also overexpress histone deacetylases (HDACs) giving rise to epigenetic patterns of chemoresistance and to acetylation of other regulatory proteins, as well. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies. Thus, natural compounds as well as novel synthetic drugs are considered to be used in single or combined therapy of PDAC. A number of proteasome and HDAC inhibitors or selective inhibitors of IKK, EGFR, Akt and mTOR have been widely explored in preclinical settings and clinical studies. Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing yet. Thus, new molecular targets and novel concepts of combination therapies need to get access into clinical trials – either in neoadjuvant/adjuvant or in palliative treatments. |
doi_str_mv | 10.1016/j.canlet.2010.10.015 |
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Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resistance to apoptotic stimuli such as death ligands (FasL, TRAIL) or anti-cancer drugs (gemcitabine) by a great number of molecular alterations either disrupting an apoptosis inducing signal or counteracting the execution of apoptosis. Thus, PDAC cells exhibit alterations in the EGFR/MAPK/Ras/raf1-, PI3K/Akt-, TRAIL/TRAF2-, or IKK/NF-κB pathway accompanied by deregulations in the expression of apoptosis regulators such as cIAP, Bcl2, XIAP or survivin. Along with protection against apoptosis, PDAC cells also overexpress histone deacetylases (HDACs) giving rise to epigenetic patterns of chemoresistance and to acetylation of other regulatory proteins, as well. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies. Thus, natural compounds as well as novel synthetic drugs are considered to be used in single or combined therapy of PDAC. A number of proteasome and HDAC inhibitors or selective inhibitors of IKK, EGFR, Akt and mTOR have been widely explored in preclinical settings and clinical studies. Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing yet. Thus, new molecular targets and novel concepts of combination therapies need to get access into clinical trials – either in neoadjuvant/adjuvant or in palliative treatments.</description><identifier>ISSN: 0304-3835</identifier><identifier>EISSN: 1872-7980</identifier><identifier>DOI: 10.1016/j.canlet.2010.10.015</identifier><identifier>PMID: 21078544</identifier><language>eng</language><publisher>Ireland: Elsevier Ireland Ltd</publisher><subject>acetylation ; adenocarcinoma ; Animals ; Anti-cancer therapy ; antineoplastic agents ; Apoptosis ; Cancer therapies ; Carcinoma, Pancreatic Ductal - drug therapy ; Carcinoma, Pancreatic Ductal - pathology ; Chemoresistance ; Chemotherapy ; clinical trials ; death ; Deoxycytidine - analogs & derivatives ; Deoxycytidine - therapeutic use ; Drug Resistance, Neoplasm ; epigenetics ; Hematology, Oncology and Palliative Medicine ; Histone Deacetylases - metabolism ; histones ; Humans ; MAP Kinase Signaling System ; MicroRNAs - metabolism ; NF-kappa B - metabolism ; Pancreatic cancer ; pancreatic neoplasms ; Pancreatic Neoplasms - drug therapy ; Pancreatic Neoplasms - pathology ; Pharmaceutical industry ; Programmed cell death ; proteasome endopeptidase complex ; Proteasome Inhibitors - pharmacology ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-raf - metabolism ; ras Proteins - metabolism ; Receptor, Epidermal Growth Factor - metabolism ; regulatory proteins ; therapeutics ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Cancer letters, 2013-05, Vol.332 (2), p.346-358</ispartof><rights>Elsevier Ireland Ltd</rights><rights>2010 Elsevier Ireland Ltd</rights><rights>Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited May 28, 2013</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c469t-e7077a311aa601a9dd5d64fecc565999dcef6746788ee2af1f505175759449bd3</citedby><cites>FETCH-LOGICAL-c469t-e7077a311aa601a9dd5d64fecc565999dcef6746788ee2af1f505175759449bd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.canlet.2010.10.015$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21078544$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arlt, Alexander</creatorcontrib><creatorcontrib>Müerköster, Susanne Sebens</creatorcontrib><creatorcontrib>Schäfer, Heiner</creatorcontrib><title>Targeting apoptosis pathways in pancreatic cancer</title><title>Cancer letters</title><addtitle>Cancer Lett</addtitle><description>Pancreatic cancer – here in particular pancreatic ductal adenocarcinoma (PDAC) – is still a highly therapy refractory disease. Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resistance to apoptotic stimuli such as death ligands (FasL, TRAIL) or anti-cancer drugs (gemcitabine) by a great number of molecular alterations either disrupting an apoptosis inducing signal or counteracting the execution of apoptosis. Thus, PDAC cells exhibit alterations in the EGFR/MAPK/Ras/raf1-, PI3K/Akt-, TRAIL/TRAF2-, or IKK/NF-κB pathway accompanied by deregulations in the expression of apoptosis regulators such as cIAP, Bcl2, XIAP or survivin. Along with protection against apoptosis, PDAC cells also overexpress histone deacetylases (HDACs) giving rise to epigenetic patterns of chemoresistance and to acetylation of other regulatory proteins, as well. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies. Thus, natural compounds as well as novel synthetic drugs are considered to be used in single or combined therapy of PDAC. A number of proteasome and HDAC inhibitors or selective inhibitors of IKK, EGFR, Akt and mTOR have been widely explored in preclinical settings and clinical studies. Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing yet. Thus, new molecular targets and novel concepts of combination therapies need to get access into clinical trials – either in neoadjuvant/adjuvant or in palliative treatments.</description><subject>acetylation</subject><subject>adenocarcinoma</subject><subject>Animals</subject><subject>Anti-cancer therapy</subject><subject>antineoplastic agents</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Carcinoma, Pancreatic Ductal - drug therapy</subject><subject>Carcinoma, Pancreatic Ductal - pathology</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>clinical trials</subject><subject>death</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxycytidine - therapeutic use</subject><subject>Drug Resistance, Neoplasm</subject><subject>epigenetics</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Histone Deacetylases - metabolism</subject><subject>histones</subject><subject>Humans</subject><subject>MAP Kinase Signaling System</subject><subject>MicroRNAs - metabolism</subject><subject>NF-kappa B - metabolism</subject><subject>Pancreatic cancer</subject><subject>pancreatic neoplasms</subject><subject>Pancreatic Neoplasms - drug therapy</subject><subject>Pancreatic Neoplasms - pathology</subject><subject>Pharmaceutical industry</subject><subject>Programmed cell death</subject><subject>proteasome endopeptidase complex</subject><subject>Proteasome Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-raf - metabolism</subject><subject>ras Proteins - metabolism</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>regulatory proteins</subject><subject>therapeutics</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>0304-3835</issn><issn>1872-7980</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1P3DAQhq2qqCzQf1C1K_XCJcs4_koulSrEl4TEYeFsDc5k6202Se1sq_33OGQpEhdOtkbPvB4_w9gXDgsOXJ-tFw7bhoZFDs-lBXD1gc14YfLMlAV8ZDMQIDNRCHXIjmJcA4CSRn1ihzkHUygpZ4zfY1jR4NvVHPuuH7ro47zH4dc_3MW5b9O9dYFw8G6e3nMUTthBjU2kz_vzmD1cXtyfX2e3d1c35z9vMyd1OWRkwBgUnCNq4FhWlaq0rMk5pVVZlpWjWhupTVEQ5VjzWoHiRhlVSlk-VuKYnU65fej-bCkOduOjo6bBlrpttFzkxuRKKJnQ72_QdbcNbZrOcq0LkErkIyUnyoUuxkC17YPfYNhZDnZUatd2UmpHpWM1KU1tX_fh28cNVf-bXhwm4NsE1NhZXAUf7cMyJajkWwhhIBE_JoKSr7-ego3OU5JZ-UBusFXn35vhbYBrfOsdNr9pR_H1tzbmFuxyXPy4dz6uHKAQTwV5pRk</recordid><startdate>20130528</startdate><enddate>20130528</enddate><creator>Arlt, Alexander</creator><creator>Müerköster, Susanne Sebens</creator><creator>Schäfer, Heiner</creator><general>Elsevier Ireland Ltd</general><general>Elsevier Limited</general><scope>FBQ</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>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20130528</creationdate><title>Targeting apoptosis pathways in pancreatic cancer</title><author>Arlt, Alexander ; Müerköster, Susanne Sebens ; Schäfer, Heiner</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c469t-e7077a311aa601a9dd5d64fecc565999dcef6746788ee2af1f505175759449bd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>acetylation</topic><topic>adenocarcinoma</topic><topic>Animals</topic><topic>Anti-cancer therapy</topic><topic>antineoplastic agents</topic><topic>Apoptosis</topic><topic>Cancer therapies</topic><topic>Carcinoma, Pancreatic Ductal - drug therapy</topic><topic>Carcinoma, Pancreatic Ductal - pathology</topic><topic>Chemoresistance</topic><topic>Chemotherapy</topic><topic>clinical trials</topic><topic>death</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxycytidine - therapeutic use</topic><topic>Drug Resistance, Neoplasm</topic><topic>epigenetics</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Histone Deacetylases - metabolism</topic><topic>histones</topic><topic>Humans</topic><topic>MAP Kinase Signaling System</topic><topic>MicroRNAs - metabolism</topic><topic>NF-kappa B - metabolism</topic><topic>Pancreatic cancer</topic><topic>pancreatic neoplasms</topic><topic>Pancreatic Neoplasms - drug therapy</topic><topic>Pancreatic Neoplasms - pathology</topic><topic>Pharmaceutical industry</topic><topic>Programmed cell death</topic><topic>proteasome endopeptidase complex</topic><topic>Proteasome Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins c-raf - metabolism</topic><topic>ras Proteins - metabolism</topic><topic>Receptor, Epidermal Growth Factor - metabolism</topic><topic>regulatory proteins</topic><topic>therapeutics</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Arlt, Alexander</creatorcontrib><creatorcontrib>Müerköster, Susanne Sebens</creatorcontrib><creatorcontrib>Schäfer, Heiner</creatorcontrib><collection>AGRIS</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>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arlt, Alexander</au><au>Müerköster, Susanne Sebens</au><au>Schäfer, Heiner</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting apoptosis pathways in pancreatic cancer</atitle><jtitle>Cancer letters</jtitle><addtitle>Cancer Lett</addtitle><date>2013-05-28</date><risdate>2013</risdate><volume>332</volume><issue>2</issue><spage>346</spage><epage>358</epage><pages>346-358</pages><issn>0304-3835</issn><eissn>1872-7980</eissn><abstract>Pancreatic cancer – here in particular pancreatic ductal adenocarcinoma (PDAC) – is still a highly therapy refractory disease. Amongst the mechanisms by which PDAC cells could escape any non-surgical therapy, anti-apoptotic protection seems to be the most relevant one. PDAC cells have acquired resistance to apoptotic stimuli such as death ligands (FasL, TRAIL) or anti-cancer drugs (gemcitabine) by a great number of molecular alterations either disrupting an apoptosis inducing signal or counteracting the execution of apoptosis. Thus, PDAC cells exhibit alterations in the EGFR/MAPK/Ras/raf1-, PI3K/Akt-, TRAIL/TRAF2-, or IKK/NF-κB pathway accompanied by deregulations in the expression of apoptosis regulators such as cIAP, Bcl2, XIAP or survivin. Along with protection against apoptosis, PDAC cells also overexpress histone deacetylases (HDACs) giving rise to epigenetic patterns of chemoresistance and to acetylation of other regulatory proteins, as well. With respect to the multitude of anti-apoptotic pathways, a great number of molecular targets might be of high potential in novel therapy strategies. Thus, natural compounds as well as novel synthetic drugs are considered to be used in single or combined therapy of PDAC. A number of proteasome and HDAC inhibitors or selective inhibitors of IKK, EGFR, Akt and mTOR have been widely explored in preclinical settings and clinical studies. Even though these early studies encouraged an application in a clinical setting, most of the trials have been rather disappointing yet. Thus, new molecular targets and novel concepts of combination therapies need to get access into clinical trials – either in neoadjuvant/adjuvant or in palliative treatments.</abstract><cop>Ireland</cop><pub>Elsevier Ireland Ltd</pub><pmid>21078544</pmid><doi>10.1016/j.canlet.2010.10.015</doi><tpages>13</tpages></addata></record> |
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subjects | acetylation adenocarcinoma Animals Anti-cancer therapy antineoplastic agents Apoptosis Cancer therapies Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - pathology Chemoresistance Chemotherapy clinical trials death Deoxycytidine - analogs & derivatives Deoxycytidine - therapeutic use Drug Resistance, Neoplasm epigenetics Hematology, Oncology and Palliative Medicine Histone Deacetylases - metabolism histones Humans MAP Kinase Signaling System MicroRNAs - metabolism NF-kappa B - metabolism Pancreatic cancer pancreatic neoplasms Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - pathology Pharmaceutical industry Programmed cell death proteasome endopeptidase complex Proteasome Inhibitors - pharmacology Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-raf - metabolism ras Proteins - metabolism Receptor, Epidermal Growth Factor - metabolism regulatory proteins therapeutics TOR Serine-Threonine Kinases - metabolism |
title | Targeting apoptosis pathways in pancreatic cancer |
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