Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes
Insulin-like growth factor-1 (IGF-1) promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R). Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3), which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthra...
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| creator | Fabbi, Patrizia Spallarossa, Paolo Garibaldi, Silvano Barisione, Chiara Mura, Marzia Altieri, Paola Rebesco, Barbara Monti, Maria Gaia Canepa, Marco Ghigliotti, Giorgio Brunelli, Claudio Ameri, Pietro |
| description | Insulin-like growth factor-1 (IGF-1) promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R). Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3), which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthracycline cardiotoxicity, we investigated the effects of the anthracycline, doxorubicin, on the IGF-1 system in H9c2 cardiomyocytes.
Besides inducing apoptosis, concentrations of doxorubicin comparable to those observed in patients after bolus infusion (0.1-1 µM) caused a progressive decrease in IGF-1R and increase in IGFBP-3 expression. Exogenous IGF-1 was capable to rescue cardiomyocytes from apoptosis triggered by 0.1 and 0.5 µM, but not 1 µM doxorubicin. The loss of response to IGF-1 was paralleled by a significant reduction in IGF-1 availability and signaling, as assessed by free hormone levels in conditioned media and Akt phosphorylation in cell lysates, respectively. Doxorubicin also dose-dependently induced p53, which is known to repress the transcription of IGF1R and induce that of IGFBP3. Pre-treatment with the p53 inhibitor, pifithrin-α, prevented apoptosis and the changes in IGF-1R and IGFBP-3 elicited by doxorubicin. The decrease in IGF-1R and increase in IGFBP-3, as well as apoptosis, were also antagonized by pre-treatment with the antioxidant agents, N-acetylcysteine, dexrazoxane, and carvedilol.
Doxorubicin down-regulates IGF-1R and up-regulates IGFBP-3 via p53 and oxidative stress in H9c2 cells. This leads to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Further studies are needed to confirm these findings in human cardiomyocytes and explore the possibility of manipulating the IGF-1 axis to protect against anthracycline cardiotoxicity. |
| doi_str_mv | 10.1371/journal.pone.0124643 |
| format | Article |
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Besides inducing apoptosis, concentrations of doxorubicin comparable to those observed in patients after bolus infusion (0.1-1 µM) caused a progressive decrease in IGF-1R and increase in IGFBP-3 expression. Exogenous IGF-1 was capable to rescue cardiomyocytes from apoptosis triggered by 0.1 and 0.5 µM, but not 1 µM doxorubicin. The loss of response to IGF-1 was paralleled by a significant reduction in IGF-1 availability and signaling, as assessed by free hormone levels in conditioned media and Akt phosphorylation in cell lysates, respectively. Doxorubicin also dose-dependently induced p53, which is known to repress the transcription of IGF1R and induce that of IGFBP3. Pre-treatment with the p53 inhibitor, pifithrin-α, prevented apoptosis and the changes in IGF-1R and IGFBP-3 elicited by doxorubicin. The decrease in IGF-1R and increase in IGFBP-3, as well as apoptosis, were also antagonized by pre-treatment with the antioxidant agents, N-acetylcysteine, dexrazoxane, and carvedilol.
Doxorubicin down-regulates IGF-1R and up-regulates IGFBP-3 via p53 and oxidative stress in H9c2 cells. This leads to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Further studies are needed to confirm these findings in human cardiomyocytes and explore the possibility of manipulating the IGF-1 axis to protect against anthracycline cardiotoxicity.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0124643</identifier><identifier>PMID: 25955698</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acetylcysteine ; AKT protein ; Animals ; Annexin A5 - metabolism ; Anthracycline ; Anthracyclines ; Antioxidants ; Antioxidants - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Biology ; Cardiomyocytes ; Cardiomyopathy ; Cardiotoxicity ; Caspase 3 - metabolism ; Caspase 7 - metabolism ; Cell Line ; Conditioning ; Deoxyribonucleic acid ; DNA ; Doxorubicin ; Doxorubicin - pharmacology ; Fibroblasts ; Flow cytometry ; Heart ; Heart cells ; In Situ Nick-End Labeling ; Insulin ; Insulin-Like Growth Factor Binding Protein 3 - metabolism ; Insulin-like growth factor I ; Insulin-Like Growth Factor I - metabolism ; Insulin-Like Growth Factor I - pharmacology ; Insulin-like growth factor-binding protein 3 ; Insulin-like growth factors ; Internal medicine ; Intracellular Space - metabolism ; Lysates ; Medicine ; Myocardium ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - metabolism ; Oxidation resistance ; Oxidative stress ; p53 Protein ; Phosphorylation ; Propidium - metabolism ; Protein binding ; Proteins ; Rats ; Razoxane ; Receptor, IGF Type 1 - metabolism ; Resistance factors ; Signal Transduction - drug effects ; Signaling ; Transcription ; Tumor proteins ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>PloS one, 2015-05, Vol.10 (5), p.e0124643</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Fabbi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2015 Fabbi et al 2015 Fabbi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-dab1652724a5f04cb45453177f80fed2bf49427acdcb20823f557c6a84d6bc233</citedby><cites>FETCH-LOGICAL-c692t-dab1652724a5f04cb45453177f80fed2bf49427acdcb20823f557c6a84d6bc233</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/PMC4425434/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425434/$$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/25955698$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mukhopadhyay, Partha</contributor><creatorcontrib>Fabbi, Patrizia</creatorcontrib><creatorcontrib>Spallarossa, Paolo</creatorcontrib><creatorcontrib>Garibaldi, Silvano</creatorcontrib><creatorcontrib>Barisione, Chiara</creatorcontrib><creatorcontrib>Mura, Marzia</creatorcontrib><creatorcontrib>Altieri, Paola</creatorcontrib><creatorcontrib>Rebesco, Barbara</creatorcontrib><creatorcontrib>Monti, Maria Gaia</creatorcontrib><creatorcontrib>Canepa, Marco</creatorcontrib><creatorcontrib>Ghigliotti, Giorgio</creatorcontrib><creatorcontrib>Brunelli, Claudio</creatorcontrib><creatorcontrib>Ameri, Pietro</creatorcontrib><title>Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Insulin-like growth factor-1 (IGF-1) promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R). Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3), which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthracycline cardiotoxicity, we investigated the effects of the anthracycline, doxorubicin, on the IGF-1 system in H9c2 cardiomyocytes.
Besides inducing apoptosis, concentrations of doxorubicin comparable to those observed in patients after bolus infusion (0.1-1 µM) caused a progressive decrease in IGF-1R and increase in IGFBP-3 expression. Exogenous IGF-1 was capable to rescue cardiomyocytes from apoptosis triggered by 0.1 and 0.5 µM, but not 1 µM doxorubicin. The loss of response to IGF-1 was paralleled by a significant reduction in IGF-1 availability and signaling, as assessed by free hormone levels in conditioned media and Akt phosphorylation in cell lysates, respectively. Doxorubicin also dose-dependently induced p53, which is known to repress the transcription of IGF1R and induce that of IGFBP3. Pre-treatment with the p53 inhibitor, pifithrin-α, prevented apoptosis and the changes in IGF-1R and IGFBP-3 elicited by doxorubicin. The decrease in IGF-1R and increase in IGFBP-3, as well as apoptosis, were also antagonized by pre-treatment with the antioxidant agents, N-acetylcysteine, dexrazoxane, and carvedilol.
Doxorubicin down-regulates IGF-1R and up-regulates IGFBP-3 via p53 and oxidative stress in H9c2 cells. This leads to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Further studies are needed to confirm these findings in human cardiomyocytes and explore the possibility of manipulating the IGF-1 axis to protect against anthracycline cardiotoxicity.</description><subject>Acetylcysteine</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Annexin A5 - metabolism</subject><subject>Anthracycline</subject><subject>Anthracyclines</subject><subject>Antioxidants</subject><subject>Antioxidants - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biology</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Cardiotoxicity</subject><subject>Caspase 3 - metabolism</subject><subject>Caspase 7 - metabolism</subject><subject>Cell Line</subject><subject>Conditioning</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Doxorubicin</subject><subject>Doxorubicin - pharmacology</subject><subject>Fibroblasts</subject><subject>Flow cytometry</subject><subject>Heart</subject><subject>Heart cells</subject><subject>In Situ Nick-End Labeling</subject><subject>Insulin</subject><subject>Insulin-Like Growth Factor Binding Protein 3 - metabolism</subject><subject>Insulin-like growth factor I</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Insulin-Like Growth Factor I - pharmacology</subject><subject>Insulin-like growth factor-binding protein 3</subject><subject>Insulin-like growth factors</subject><subject>Internal medicine</subject><subject>Intracellular Space - metabolism</subject><subject>Lysates</subject><subject>Medicine</subject><subject>Myocardium</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Oxidation resistance</subject><subject>Oxidative stress</subject><subject>p53 Protein</subject><subject>Phosphorylation</subject><subject>Propidium - metabolism</subject><subject>Protein binding</subject><subject>Proteins</subject><subject>Rats</subject><subject>Razoxane</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Resistance factors</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Transcription</subject><subject>Tumor proteins</subject><subject>Tumor Suppressor Protein p53 - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</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 China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fabbi, Patrizia</au><au>Spallarossa, Paolo</au><au>Garibaldi, Silvano</au><au>Barisione, Chiara</au><au>Mura, Marzia</au><au>Altieri, Paola</au><au>Rebesco, Barbara</au><au>Monti, Maria Gaia</au><au>Canepa, Marco</au><au>Ghigliotti, Giorgio</au><au>Brunelli, Claudio</au><au>Ameri, Pietro</au><au>Mukhopadhyay, Partha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-05-08</date><risdate>2015</risdate><volume>10</volume><issue>5</issue><spage>e0124643</spage><pages>e0124643-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Insulin-like growth factor-1 (IGF-1) promotes the survival of cardiomyocytes by activating type 1 IGF receptor (IGF-1R). Within the myocardium, IGF-1 action is modulated by IGF binding protein-3 (IGFBP-3), which sequesters IGF-1 away from IGF-1R. Since cardiomyocyte apoptosis is implicated in anthracycline cardiotoxicity, we investigated the effects of the anthracycline, doxorubicin, on the IGF-1 system in H9c2 cardiomyocytes.
Besides inducing apoptosis, concentrations of doxorubicin comparable to those observed in patients after bolus infusion (0.1-1 µM) caused a progressive decrease in IGF-1R and increase in IGFBP-3 expression. Exogenous IGF-1 was capable to rescue cardiomyocytes from apoptosis triggered by 0.1 and 0.5 µM, but not 1 µM doxorubicin. The loss of response to IGF-1 was paralleled by a significant reduction in IGF-1 availability and signaling, as assessed by free hormone levels in conditioned media and Akt phosphorylation in cell lysates, respectively. Doxorubicin also dose-dependently induced p53, which is known to repress the transcription of IGF1R and induce that of IGFBP3. Pre-treatment with the p53 inhibitor, pifithrin-α, prevented apoptosis and the changes in IGF-1R and IGFBP-3 elicited by doxorubicin. The decrease in IGF-1R and increase in IGFBP-3, as well as apoptosis, were also antagonized by pre-treatment with the antioxidant agents, N-acetylcysteine, dexrazoxane, and carvedilol.
Doxorubicin down-regulates IGF-1R and up-regulates IGFBP-3 via p53 and oxidative stress in H9c2 cells. This leads to resistance to IGF-1 that may contribute to doxorubicin-initiated apoptosis. Further studies are needed to confirm these findings in human cardiomyocytes and explore the possibility of manipulating the IGF-1 axis to protect against anthracycline cardiotoxicity.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25955698</pmid><doi>10.1371/journal.pone.0124643</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-05, Vol.10 (5), p.e0124643 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1982585746 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acetylcysteine AKT protein Animals Annexin A5 - metabolism Anthracycline Anthracyclines Antioxidants Antioxidants - pharmacology Apoptosis Apoptosis - drug effects Biology Cardiomyocytes Cardiomyopathy Cardiotoxicity Caspase 3 - metabolism Caspase 7 - metabolism Cell Line Conditioning Deoxyribonucleic acid DNA Doxorubicin Doxorubicin - pharmacology Fibroblasts Flow cytometry Heart Heart cells In Situ Nick-End Labeling Insulin Insulin-Like Growth Factor Binding Protein 3 - metabolism Insulin-like growth factor I Insulin-Like Growth Factor I - metabolism Insulin-Like Growth Factor I - pharmacology Insulin-like growth factor-binding protein 3 Insulin-like growth factors Internal medicine Intracellular Space - metabolism Lysates Medicine Myocardium Myocytes, Cardiac - drug effects Myocytes, Cardiac - metabolism Oxidation resistance Oxidative stress p53 Protein Phosphorylation Propidium - metabolism Protein binding Proteins Rats Razoxane Receptor, IGF Type 1 - metabolism Resistance factors Signal Transduction - drug effects Signaling Transcription Tumor proteins Tumor Suppressor Protein p53 - metabolism |
| title | Doxorubicin impairs the insulin-like growth factor-1 system and causes insulin-like growth factor-1 resistance in cardiomyocytes |
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