Article ; Online: The WD repeat-containing protein 5 (WDR5) antagonist WDR5-0103 restores the efficacy of cytotoxic drugs in multidrug-resistant cancer cells overexpressing ABCB1 or ABCG2.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
2022 Volume 154, Page(s) 113663
Abstract: The development of multidrug resistance (MDR) is one of the major challenges in the treatment of cancer which is caused by the overexpression of the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein) and/or ABCG2 (BCRP/MXR/ABCP) in cancer ... ...
| Abstract | The development of multidrug resistance (MDR) is one of the major challenges in the treatment of cancer which is caused by the overexpression of the ATP-binding cassette (ABC) transporters ABCB1 (P-glycoprotein) and/or ABCG2 (BCRP/MXR/ABCP) in cancer cells. These transporters are capable of reducing the efficacy of cytotoxic drugs by actively effluxing them out of cancer cells. Since there is currently no approved treatment for patients with multidrug-resistant tumors, the drug repurposing approach provides an alternative route to identify agents to reverse MDR mediated by ABCB1 and/or ABCG2 in multidrug-resistant cancer cells. WDR5-0103 is a histone H3 lysine 4 (H3K4) methyltransferase inhibitor that disrupts the interaction between the WD repeat-containing protein 5 (WDR5) and mixed-lineage leukemia (MLL) protein. In this study, the effect of WDR5-0103 on MDR mediated by ABCB1 and ABCG2 was determined. We found that in a concentration-dependent manner, WDR5-0103 could sensitize ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to conventional cytotoxic drugs. Our results showed that WDR5-0103 reverses MDR and improves drug-induced apoptosis in multidrug-resistant cancer cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, without altering the protein expression of ABCB1 or ABCG2. The potential sites of interactions of WDR5-0103 with the drug-binding pockets of ABCB1 and ABCG2 were predicted by molecular docking. In conclusion, the MDR reversal activity of WDR5-0103 demonstrated here indicates that it could be used in combination therapy to provide benefits to a subset of patients with tumor expressing high levels of ABCB1 or ABCG2. |
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| MeSH term(s) | ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; ATP-Binding Cassette Transporters ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Molecular Docking Simulation ; Neoplasm Proteins/metabolism ; Neoplasms ; WD40 Repeats | |||||
| Chemical Substances | ABCB1 protein, human ; ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; ATP-Binding Cassette Transporters ; Antineoplastic Agents ; Intracellular Signaling Peptides and Proteins ; Neoplasm Proteins ; WDR5 protein, human | |||||
| Language | English | |||||
| Publishing date | 2022-09-05 | |||||
| Publishing country | France | |||||
| Document type | Journal Article | |||||
| ZDB-ID | 392415-4 | |||||
| ISSN | 1950-6007 ; 0753-3322 ; 0300-0893 | |||||
| ISSN (online) | 1950-6007 | |||||
| ISSN | 0753-3322 ; 0300-0893 | |||||
| DOI | 10.1016/j.biopha.2022.113663 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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