Inhibitory Effect of Dextran Derivatives on Multidrug Resistance-Related Efflux Transporters in Vitro

Kaori Morimoto, Makoto Ishii, Yoshikazu Sugimoto, Takuo Ogihara, Mikio Tomita

研究成果: Article査読

抄録

Dextran is a promising candidate as a nanocarrier of chemotherapeutic drugs due to its biocompatibility, biodegradability, and ability to accumulate in tumors. Furthermore, dextran derivatives interact with P-glycoprotein (P-gp), so we hypothesized that they may be available as tumor-specific drug delivery systems with the ability to reverse multidrug resistance. Here, to test this idea, we investigated whether dextran and its derivatives inhibit breast cancer resistance protein (BCRP), multidrug resistance associated protein 1 (MRP1), and P-gp in vitro. First, we examined their effect on the uptake of specific fluorescent substrates by inside-out Sf-9 membrane vesicles overexpressing BCRP, MRP1, and P-gp. BCRP and MRP1 were significantly inhibited by 2-hydroxypropyl-trimethylammonium-dextran of 4 and 70kDa (Q-D4 and Q-D70) at a concentration near the clinically used concentration of dextran; however, P-gp was not inhibited. A structure–activity study showed that Q-D4, Q-D70, and 40kDa diethylaminoethyl-dextran (DEAE-D40) significantly inhibited BCRP, while 4, 40, and 70kDa dextrans (D4, D40, and D70), dextran sulfate (Sul-D40), and the individual saccharide components of dextran did not. These results suggest that the cationic side chains, but not the saccharides, are important for BCRP inhibition. Finally, cell-based efflux assay was conducted. Q-D4, Q-D70, and DEAE-D40 did not specifically increase the retention of Hoechst33342 in BCRP-overexpressing KB cells. Similarly, Q-D4 and Q-D70 did not affect the intracellular retention of specific fluorescent substrates in MRP1- and P-gp-overexpressing KB cells. The ineffectiveness in cellular systems is presumably due to inability of the dextran derivatives to access transporters located on the cytoplasmic side of the cell membrane.

本文言語English
ページ(範囲)1036-1042
ページ数7
ジャーナルBiological and Pharmaceutical Bulletin
45
8
DOI
出版ステータスPublished - 2022 8月

ASJC Scopus subject areas

  • 薬理学
  • 薬科学

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