Polyoxovanadates as new P-glycoprotein inhibitors: insights into the mechanism of inhibition.

Autor: Kita DH; Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná, Curitiba, Brazil.; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., de Andrade GA; Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná, Curitiba, Brazil., Missina JM; Department of Chemistry, Federal University of Paraná, Curitiba, Brazil., Postal K; Department of Chemistry, Federal University of Paraná, Curitiba, Brazil., Boell VK; Department of Chemistry, Federal University of Paraná, Curitiba, Brazil., Santana FS; Department of Chemistry, Federal University of Paraná, Curitiba, Brazil., Zattoni IF; Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná, Curitiba, Brazil., Zanzarini IDS; Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná, Curitiba, Brazil., Moure VR; Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná, Curitiba, Brazil.; Department of Clinical Analysis, Federal University of Paraná, Curitiba, Brazil., Rego FGM; Department of Clinical Analysis, Federal University of Paraná, Curitiba, Brazil., Picheth G; Department of Clinical Analysis, Federal University of Paraná, Curitiba, Brazil., de Souza EM; Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Brazil., Mitchell DA; Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Brazil., Ambudkar SV; Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA., Nunes GG; Department of Chemistry, Federal University of Paraná, Curitiba, Brazil., Valdameri G; Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná, Curitiba, Brazil.; Department of Clinical Analysis, Federal University of Paraná, Curitiba, Brazil.
Jazyk: angličtina
Zdroj: FEBS letters [FEBS Lett] 2022 Feb; Vol. 596 (3), pp. 381-399. Date of Electronic Publication: 2021 Dec 30.
DOI: 10.1002/1873-3468.14265
Abstrakt: A promising strategy to overcome multidrug resistance is the use of inhibitors of ABC drug transporters. For this reason, we evaluated the polyoxovanadates (POVs) [V 10 O 28 ] 6- (V 10 ), [H 6 V 14 O 38 (PO 4 )] 5- (V 14 ), [V 15 O 36 Cl] 6- (V 15 ) and [V 18 O 42 I] 7- (V 18 ) as inhibitors of three major multidrug resistance-linked ABC transporters: P-glycoprotein (P-gp), ABCG2 and MRP1. All of the POVs selectively inhibited P-gp. V 10 and V 18 were the two most promising compounds, with IC 50 values of transport inhibition of 25.4 and 22.7 µm, respectively. Both compounds inhibited P-gp ATPase activity, with the same IC 50 value of 1.26 µm. V 10 and V 18 triggered different conformational changes in the P-gp protein with time-dependent inhibition, which was confirmed using the synthesized salt of V 10 with rhodamine B, RhoB-V 10 . The hydrophilic nature of POVs supports the hypothesis that these compounds target an unusual ligand-binding site, opening new possibilities in the development of potent modulators of ABC transporters.
(© 2021 Federation of European Biochemical Societies.)
Databáze: MEDLINE
Externí odkaz: