Identification of Novel Anthracycline Resistance Genes and Their Inhibitors

Publication type:
Journal article
Metadata:
Autoren
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000714516600001&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.3390/ph14101051
eISSN
1424-8247
Externe Identifier
  • Clarivate Analytics Document Solution ID: WR5CE
  • PubMed Identifier: 34681275
Ausgabe der Veröffentlichung
10
Zeitschrift
PHARMACEUTICALS
Schlüsselwörter
  • cancer
  • chemotherapy
  • drug resistance
  • RNA sequencing
  • transfection
Artikelnummer
ARTN 1051
Datum der Veröffentlichung
2021
Status
Published
Titel
Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
Sub types
  • Article
Ausgabe der Zeitschrift
14

Data source: Web of Science (Lite)

Other metadata sources:
Abstract
<jats:p>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.</jats:p>
Autoren
DOI
10.3390/ph14101051
eISSN
1424-8247
Ausgabe der Veröffentlichung
10
Zeitschrift
Pharmaceuticals
Sprache
en
Online publication date
2021
Paginierung
1051 - 1051
Status
Published online
Herausgeber
MDPI AG
Herausgeber URL
http://dx.doi.org/10.3390/ph14101051
Datum der Datenerfassung
2021
Titel
Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
Ausgabe der Zeitschrift
14

Data source: Crossref

Abstract
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. <i>HMOX1</i>, <i>NEIL2</i>, and <i>PRKCA</i> 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 <i>HMOX1</i>- and <i>PRKCA</i>-transfected cell lines. Bexarotene treatment had a comparable doxorubicin-sensitizing effect in <i>HMOX1</i>-transfected cells and desloratadine in <i>PRKCA</i>-transfected cells. Novel drug resistance mechanisms independent of ABC transporters have been identified that contribute to anthracycline resistance in MDR cells.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Autoren
DOI
10.3390/ph14101051
eISSN
1424-8247
Externe Identifier
  • PubMed Identifier: 34681275
  • PubMed Central ID: PMC8540045
Open access
true
ISSN
1424-8247
Ausgabe der Veröffentlichung
10
Zeitschrift
Pharmaceuticals (Basel, Switzerland)
Sprache
eng
Medium
Electronic
Online publication date
2021
Open access status
Open Access
Paginierung
1051
Datum der Veröffentlichung
2021
Status
Published
Publisher licence
CC BY
Datum der Datenerfassung
2021
Titel
Identification of Novel Anthracycline Resistance Genes and Their Inhibitors.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
14

Files

https://www.mdpi.com/1424-8247/14/10/1051/pdf?version=1634711087 https://europepmc.org/articles/PMC8540045?pdf=render

Data source: Europe PubMed Central

Abstract
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.
Date of acceptance
2021
Autoren
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/34681275
DOI
10.3390/ph14101051
Externe Identifier
  • PubMed Central ID: PMC8540045
ISSN
1424-8247
Ausgabe der Veröffentlichung
10
Zeitschrift
Pharmaceuticals (Basel)
Schlüsselwörter
  • RNA sequencing
  • cancer
  • chemotherapy
  • drug resistance
  • transfection
Sprache
eng
Country
Switzerland
PII
ph14101051
Datum der Veröffentlichung
2021
Status
Published online
Titel
Identification of Novel Anthracycline Resistance Genes and Their Inhibitors.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
14

Data source: PubMed

Beziehungen:
Property of

Tools