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Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were...

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Autores principales: Kadioglu, Onat, Elbadawi, Mohamed, Fleischer, Edmond, Efferth, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540045/
https://www.ncbi.nlm.nih.gov/pubmed/34681275
http://dx.doi.org/10.3390/ph14101051
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author Kadioglu, Onat
Elbadawi, Mohamed
Fleischer, Edmond
Efferth, Thomas
author_facet Kadioglu, Onat
Elbadawi, Mohamed
Fleischer, Edmond
Efferth, Thomas
author_sort Kadioglu, Onat
collection PubMed
description Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.
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spelling pubmed-85400452021-10-24 Identification of Novel Anthracycline Resistance Genes and Their Inhibitors Kadioglu, Onat Elbadawi, Mohamed Fleischer, Edmond Efferth, Thomas Pharmaceuticals (Basel) Article Differentially expressed genes have been previously identified by us in multidrug-resistant tumor cells mainly resistant to doxorubicin. In the present study, we exemplarily focused on some of these genes to investigate their causative relationship with drug resistance. HMOX1, NEIL2, and PRKCA were overexpressed by lentiviral-plasmid-based transfection of HEK293 cells. An in silico drug repurposing approach was applied using virtual screening and molecular docking of FDA-approved drugs to identify inhibitors of these new drug-resistant genes. Overexpression of the selected genes conferred resistance to doxorubicin and daunorubicin but not to vincristine, docetaxel, and cisplatin, indicating the involvement of these genes in resistance to anthracyclines but not to a broader MDR phenotype. Using virtual drug screening and molecular docking analyses, we identified FDA-approved compounds (conivaptan, bexarotene, and desloratadine) that were interacting with HMOX1 and PRKCA at even stronger binding affinities than 1-(adamantan-1-yl)-2-(1H-imidazol-1-yl)ethenone and ellagic acid as known inhibitors of HMOX1 and PRKCA, respectively. Conivaptan treatment increased doxorubicin sensitivity of both HMOX1- and PRKCA-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in HMOX1-transfected cells and desloratadine in PRKCA-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells. MDPI 2021-10-16 /pmc/articles/PMC8540045/ /pubmed/34681275 http://dx.doi.org/10.3390/ph14101051 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kadioglu, Onat
Elbadawi, Mohamed
Fleischer, Edmond
Efferth, Thomas
Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
title Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
title_full Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
title_fullStr Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
title_full_unstemmed Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
title_short Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
title_sort identification of novel anthracycline resistance genes and their inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540045/
https://www.ncbi.nlm.nih.gov/pubmed/34681275
http://dx.doi.org/10.3390/ph14101051
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