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

FEBS Letters

article

Diogo Henrique Kita¹  Gisele Alves de Andrade¹  Juliana Morais Missina³  Kahoana Postal³  Viktor Kalbermatter Boell³  Francielli Sousa Santana³  Ingrid Fatima Zattoni¹  Isadora da Silva Zanzarini¹  Vivian Rotuno Moure¹  Fabiane Gomes de Moraes Rego⁴  Geraldo Picheth⁴  Emanuel Maltempi de Souza⁵  David A. Mitchell⁵  Suresh V. Ambudkar²  Giovana Gioppo Nunes³  Glaucio Valdameri¹ 

[1] Pharmaceutical Sciences Graduate Program, Laboratory of Cancer Drug Resistance, Federal University of Paraná;Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health;Department of Chemistry, Federal University of Paraná;Department of Clinical Analysis, Federal University of Paraná;Department of Biochemistry and Molecular Biology, Federal University of Paraná

关键词: ABC transporters;    cancer;    inhibitors;    multidrug resistance;    P-glycoprotein;    polyoxovanadates;   

DOI  :  10.1002/1873-3468.14265

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 µ m , respectively. Both compounds inhibited P-gp ATPase activity, with the same IC 50 value of 1.26 µ m . 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.

【 授权许可】

Unknown