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Reversal of P-gp and BCRP-mediated MDR by tariquidar derivatives.

Abstract：

:With an aim to generate non-toxic, specific and highly potent multidrug resistance (MDR) modulators, a novel series of anthranilic acid amide-substituted tariquidar derivatives were synthesized. The new compounds were evaluated for their cytotoxicity toward normal human colon fibroblasts (CCD18-Co), human gastric epithelial cell line (HFE) and primary rat liver cells, and for their ability to inhibit P-gp/BCRP-mediated drug efflux and reversal of P-gp and BCRP-mediated MDR in parental and drug-resistant cancer cell lines (LCC6 MDR1, MCF-7 FLV1000, R-HepG2, SW620-Ad300). While tariquidar is highly toxic to normal cells, the new derivatives exhibited much lower or negligible cytotoxicity. Some of the new tariquidar derivatives inhibited both P-gp and BCRP-mediated drug efflux whereas a few of them bearing a sulfonamide functional group (1, 5, and 16) are specific to P-gp. The new compounds were also found to potentiate the anticancer activity of the transporter substrate anticancer drugs in the corresponding transporter-overexpressing cell lines. The extent of resistance reversal was found to be consistent with the transporter inhibitory effect of the new derivatives. To further understand the mechanism of P-gp and BCRP inhibition, the tariquidar derivatives were found to interact with the transporters using an antibody-based UIC2 or 5D3 shift assay. Moreover, the transporters-inhibiting derivatives were found to modulate the ATPase activities of the two MDR transporters. Our data thus advocate further development of the new compounds for the circumvention of MDR.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Li XQ,Wang L,Lei Y,Hu T,Zhang FL,Cho CH,To KK

doi

10.1016/j.ejmech.2015.06.049

subject

Has Abstract

pub_date

2015-08-28 00:00:00

pages

560-72

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(15)30128-8

journal_volume

101

pub_type

杂志文章

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