Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model

Doxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of the drug. Resveratrol (Rsv) has been tested a...

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Autores:
Vargas, José Eduardo
Puga, Renato
Lenz, Guido
Trindade, Cristiano
Filippi-Chiela, Eduardo
Tipo de recurso:
Fecha de publicación:
2020
Institución:
Universidad Simón Bolívar
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Repositorio Digital USB
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eng
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oai:bonga.unisimon.edu.co:20.500.12442/6761
Acceso en línea:
https://hdl.handle.net/20.500.12442/6761
https://doi.org/10.1155/2020/5432651
https://www.hindawi.com/journals/omcl/2020/5432651/
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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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oai_identifier_str oai:bonga.unisimon.edu.co:20.500.12442/6761
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dc.title.eng.fl_str_mv Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
title Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
spellingShingle Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
title_short Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
title_full Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
title_fullStr Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
title_full_unstemmed Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
title_sort Cellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico model
dc.creator.fl_str_mv Vargas, José Eduardo
Puga, Renato
Lenz, Guido
Trindade, Cristiano
Filippi-Chiela, Eduardo
dc.contributor.author.none.fl_str_mv Vargas, José Eduardo
Puga, Renato
Lenz, Guido
Trindade, Cristiano
Filippi-Chiela, Eduardo
description Doxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of the drug. Resveratrol (Rsv) has been tested as an adjuvant in mammary malignancies. However, the cellular and molecular mechanisms underlying the effects of cotreatment with Doxo and Rsv in breast cancer are poorly understood. Here, we combined in vitro and in silico analysis to characterize these mechanisms. In vitro, we employed a clinically relevant experimental design consisting of acute (24 h) treatment followed by 15 days of analysis. Acute Rsv potentiated the long-lasting effect of Doxo through the induction of apoptosis and senescence. Cells that survived to the cotreatment triggered high levels of autophagy. Autophagy inhibition during its peak of activation but not concomitant with Doxo+Rsv increased the long-term toxicity of the cotreatment. To uncover key proteins potentially associated with in vitro effects, an in silico multistep strategy was implemented. Chemical-protein networks were predicted based on constitutive gene expression of MCF7 cells and interatomic data from breast cancer. Topological analysis, KM survival analysis, and a quantitative model based on the connectivity between apoptosis, senescence, and autophagy were performed. We found seven putative genes predicted to be modulated by Rsv in the context of Doxo treatment: CCND1, CDH1, ESR1, HSP90AA1, MAPK3, PTPN11, and RPS6KB1. Six out of these seven genes have been experimentally proven to be modulated by Rsv in cancer cells, with 4 of the 6 genes in MCF7 cells. In conclusion, acute Rsv potentiated the long-term toxicity of Doxo in breast cancer potentially through the modulation of genes and mechanisms involved in Doxo resistance. Rational autophagy inhibition potentiated the effects of Rsv+Doxo, a strategy that should be further tested in animal models.
publishDate 2020
dc.date.accessioned.none.fl_str_mv 2020-11-05T17:55:44Z
dc.date.available.none.fl_str_mv 2020-11-05T17:55:44Z
dc.date.issued.none.fl_str_mv 2020
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dc.identifier.doi.none.fl_str_mv https://doi.org/10.1155/2020/5432651
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identifier_str_mv 19420994
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https://www.hindawi.com/journals/omcl/2020/5432651/
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dc.rights.*.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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dc.source.eng.fl_str_mv Oxidative Medicine and Cellular Longevity
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spelling Vargas, José Eduardo416f0def-6df6-4f2d-ad69-3c969af5664dPuga, Renato27951978-47c5-484c-a747-a0d418c2eb19Lenz, Guido46ea5e9c-875b-4eac-ba9f-1df73d830e75Trindade, Cristiano30b50065-9290-4b8a-837b-01634d3219d7Filippi-Chiela, Eduardo869c9e6c-3e06-445d-8891-f7ad72cafff12020-11-05T17:55:44Z2020-11-05T17:55:44Z202019420994https://hdl.handle.net/20.500.12442/6761https://doi.org/10.1155/2020/5432651https://www.hindawi.com/journals/omcl/2020/5432651/Doxorubicin (Doxo) is the most effective chemotherapeutic agent for the treatment of breast cancer. However, resistance to Doxo is common. Adjuvant compounds capable of modulating mechanisms involved in Doxo resistance may potentiate the effectiveness of the drug. Resveratrol (Rsv) has been tested as an adjuvant in mammary malignancies. However, the cellular and molecular mechanisms underlying the effects of cotreatment with Doxo and Rsv in breast cancer are poorly understood. Here, we combined in vitro and in silico analysis to characterize these mechanisms. In vitro, we employed a clinically relevant experimental design consisting of acute (24 h) treatment followed by 15 days of analysis. Acute Rsv potentiated the long-lasting effect of Doxo through the induction of apoptosis and senescence. Cells that survived to the cotreatment triggered high levels of autophagy. Autophagy inhibition during its peak of activation but not concomitant with Doxo+Rsv increased the long-term toxicity of the cotreatment. To uncover key proteins potentially associated with in vitro effects, an in silico multistep strategy was implemented. Chemical-protein networks were predicted based on constitutive gene expression of MCF7 cells and interatomic data from breast cancer. Topological analysis, KM survival analysis, and a quantitative model based on the connectivity between apoptosis, senescence, and autophagy were performed. We found seven putative genes predicted to be modulated by Rsv in the context of Doxo treatment: CCND1, CDH1, ESR1, HSP90AA1, MAPK3, PTPN11, and RPS6KB1. Six out of these seven genes have been experimentally proven to be modulated by Rsv in cancer cells, with 4 of the 6 genes in MCF7 cells. In conclusion, acute Rsv potentiated the long-term toxicity of Doxo in breast cancer potentially through the modulation of genes and mechanisms involved in Doxo resistance. Rational autophagy inhibition potentiated the effects of Rsv+Doxo, a strategy that should be further tested in animal models.pdfengHindawiAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Oxidative Medicine and Cellular LongevityCellular mechanisms triggered by the cotreatment of resveratrol and doxorubicin in breast cancer: A translational in vitro–In silico modelinfo:eu-repo/semantics/articleArtículo científicohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_2df8fbb1L. A. Torre, F. Islami, R. L. Siegel, E. M. Ward, and A. Jemal, “Global cancer in women: burden and trends,” Cancer Epidemiology, Biomarkers & Prevention, vol. 26, no. 4, pp. 444– 457, 2017.O. Abe, R. Abe, K. Enomoto, K. Kikuchi, H. 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Sahin, “Resveratrol protects quail hepatocytes against heat stress: modulation of the Nrf2 transcription factor and heat shock proteins,” Journal of Animal Physiology and Animal Nutrition, vol. 96, no. 1, pp. 66–74, 2012.ORIGINALPDF.pdfPDF.pdfPDFapplication/pdf9705757https://bonga.unisimon.edu.co/bitstreams/4874ba94-23b7-448f-af72-7fe0ef622a92/download5b445794b89cef77bcc38d8ea9874957MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-8381https://bonga.unisimon.edu.co/bitstreams/1a40dd1f-5e6a-4bf4-8b9e-cb0ed07560e1/download733bec43a0bf5ade4d97db708e29b185MD53CC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-8805https://bonga.unisimon.edu.co/bitstreams/d91817e0-9269-400c-89eb-c54179d5772f/download4460e5956bc1d1639be9ae6146a50347MD52TEXTCellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer A translational in vitro-in silico model.pdf.txtCellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer A translational in vitro-in silico model.pdf.txtExtracted texttext/plain98891https://bonga.unisimon.edu.co/bitstreams/79f517a4-c246-4fa6-90b6-f0c6181f58f0/downloadf6739d98c69ed53d48ad946faafd8b9aMD54PDF.pdf.txtPDF.pdf.txtExtracted texttext/plain101144https://bonga.unisimon.edu.co/bitstreams/e0b98c75-b522-44cc-b8c7-59b12cb18ffe/download0e8ba9b88304756eff623bd98cae8c06MD56THUMBNAILCellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer A translational in vitro-in silico model.pdf.jpgCellular Mechanisms Triggered by the Cotreatment of Resveratrol and Doxorubicin in Breast Cancer A translational in vitro-in silico model.pdf.jpgGenerated Thumbnailimage/jpeg1617https://bonga.unisimon.edu.co/bitstreams/f6c75568-38ce-4931-9274-be7622d2d0bd/download46dd0a23a51209cebd423ee444cac591MD55PDF.pdf.jpgPDF.pdf.jpgGenerated Thumbnailimage/jpeg5662https://bonga.unisimon.edu.co/bitstreams/4d420d49-8adf-47ed-9824-4154346fce60/downloada6a8ad12522728a363ac732bbbd0265fMD5720.500.12442/6761oai:bonga.unisimon.edu.co:20.500.12442/67612024-08-14 21:52:56.311http://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internacionalopen.accesshttps://bonga.unisimon.edu.coRepositorio Digital Universidad Simón Bolívarrepositorio.digital@unisimon.edu.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