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Belhadj, Zakia; Akther, Thamina; Wang, Zhengqiang; Xie, Jiashu
Biomedicine & pharmacotherapy, September 2024, 2024-09-00, 20240901, 2024-09-01, Letnik: 178Journal Article
Selective inhibition of overexpressed ATP binding cassette (ABC) transporters is an attractive approach to enhancing the efficacy of chemotherapeutics in multidrug resistant cancers. Previously, we reported that the cancer sensitizing effect of deazaflavin analogs, an important chemotype for developing combination treatments with topoisomerase II (TOP2) poisons, is associated with increased intracellular drug accumulation. Here we report the characterization of ZW-1226, a deazaflavin analog, as a potent inhibitor of multidrug resistance-associated protein 1 (MRP1). Specifically, ZW-1226 inhibited MRP1 with a 16-fold higher potency than the most widely used positive control MK-571 in vesicular transport assay and displayed excellent selectivity indices exceeding 100 over other major ABC transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), MRP2 and MRP3. Mechanistically, we revealed that its MRP1 inhibitory action requires the participation of GSH. In chemo-sensitization test, ZW-1226 fully reversed the MRP1-mediated drug resistance to TOP2 poisons etoposide (ETP) and doxorubicin (DOX) in H69AR cells and conferred CC50s comparable to those in the sensitive parental NCI-H69 cells. The sensitization was associated with boosted intracellular accumulation of ETP and DOX and elevated endogenous GSH. Moreover, ZW-1226 showed potential to occupy the leukotriene C4 binding site in molecular docking with bovine MRP1, presumably with the help of GSH. Lastly, ZW-1226 exhibited high tissue to plasma partitions in mice but did not alter ETP distribution to normal tissues, suggesting it could be a viable lead with desirable pharmacokinetic properties to warrant further investigation. Display omitted •Deazaflavin analog ZW-1226 is 16 times more potent than the known MRP1 inhibitor MK-571 in vesicular transport assay.•ZW-1226 showed good selectivity for MRP1 over other major ABC transporters, including P-gp, BCRP, MRP2 and MRP3.•The inhibition of MRP1 by ZW-1226 is GSH dependent.•ZW-1226 effectively reversed MRP1-mediated drug resistance to TOP2 poisons etoposide and doxorubicin in H69AR cells.•ZW-1226 exhibited high tissue to plasma partitioning in mice without altering etoposide distribution to normal tissues.
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