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Identification of Novel Anthracycline Resistance Genes and Their Inhibitors
Onat Kadioglu1, Mohamed Elbadawi1, Edmond Fleischer2
1Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
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.
Insights
New genes like HMOX1 and PRKCA contribute to multidrug resistance (MDR) in cancer cells, specifically to anthracyclines. Researchers identified FDA-approved drugs that can overcome this resistance, offering potential new therapeutic strategies for MDR tumors.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Multidrug resistance (MDR) in cancer poses a significant clinical challenge, often mediated by ABC transporters.
- Previous studies identified differentially expressed genes in doxorubicin-resistant cells, suggesting novel resistance mechanisms beyond ABC transporters.
Purpose of the Study:
- To investigate the causative role of specific genes (HMOX1, NEIL2, PRKCA) in doxorubicin resistance.
- To identify FDA-approved drugs that can inhibit these newly identified drug-resistance genes using an in silico drug repurposing approach.
Main Methods:
- Overexpression of HMOX1, NEIL2, and PRKCA in HEK293 cells via lentiviral transfection.
- In silico virtual screening and molecular docking of FDA-approved drugs against the target genes.
- Assessment of drug sensitivity in transfected cell lines following treatment with identified compounds.
Main Results:
- Overexpression of HMOX1, NEIL2, and PRKCA conferred resistance specifically to anthracyclines (doxorubicin, daunorubicin), not other chemotherapeutics.
- Virtual screening identified conivaptan, bexarotene, and desloratadine as potent inhibitors of HMOX1 and PRKCA.
- Conivaptan, bexarotene, and desloratadine treatments restored doxorubicin sensitivity in the respective transfected cell lines.
Conclusions:
- HMOX1, NEIL2, and PRKCA are involved in anthracycline resistance, independent of ABC transporter mechanisms.
- FDA-approved drugs like conivaptan, bexarotene, and desloratadine show potential for overcoming this specific type of MDR.
- These findings offer novel therapeutic avenues for treating multidrug-resistant cancers.
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