Article ; Online: Effective targeting of breast cancer by the inhibition of P-glycoprotein mediated removal of toxic lipid peroxidation byproducts from drug tolerant persister cells.
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
2023 Volume 71, Page(s) 101007
Abstract: Therapy resistance has long been considered to occur through the selection of pre-existing clones equipped to survive and quickly regrow, or through the acquisition of mutations during chemotherapy. Here we show that following in vitro treatment by ... ...
| Abstract | Therapy resistance has long been considered to occur through the selection of pre-existing clones equipped to survive and quickly regrow, or through the acquisition of mutations during chemotherapy. Here we show that following in vitro treatment by chemotherapy, epithelial breast cancer cells adopt a transient drug tolerant phenotype characterized by cell cycle arrest, epithelial-to-mesenchymal transition (EMT) and the reversible upregulation of the multidrug resistance (MDR) efflux transporter P-glycoprotein (P-gp). The drug tolerant persister (DTP) state is reversible, as cells eventually resume proliferation, giving rise to a cell population resembling the initial, drug-naïve cell lines. However, recovery after doxorubicin treatment is almost completely eliminated when DTP cells are cultured in the presence of the P-gp inhibitor Tariquidar. Mechanistically, P-gp contributes to the survival of DTP cells by removing reactive oxygen species-induced lipid peroxidation products resulting from doxorubicin exposure. In vivo, prolonged administration of Tariquidar during doxorubicin treatment holidays resulted in a significant increase of the overall survival of Brca1 |
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| MeSH term(s) | Humans ; Animals ; Mice ; Female ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ; Lipid Peroxidation ; Pharmaceutical Preparations ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; ATP Binding Cassette Transporter, Subfamily B/genetics ; Doxorubicin/pharmacology |
| Chemical Substances | ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Pharmaceutical Preparations ; ATP Binding Cassette Transporter, Subfamily B ; Doxorubicin (80168379AG) |
| Language | English |
| Publishing date | 2023-09-17 |
| Publishing country | Scotland |
| Document type | Journal Article |
| ZDB-ID | 1474513-6 |
| ISSN | 1532-2084 ; 1368-7646 |
| ISSN (online) | 1532-2084 |
| ISSN | 1368-7646 |
| DOI | 10.1016/j.drup.2023.101007 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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