Open AccessReversal of P‐glycoprotein‐mediated multidrug resistance in vitro by doramectin and nemadectin
Author(s) -
Gao Aili,
Wang Xiangjing,
Xiang Wensheng,
Liang Hongsheng,
Gao Jiguo,
Yan Yijun
Publication year - 2010
Publication title -
journal of pharmacy and pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.745
H-Index - 118
eISSN - 2042-7158
pISSN - 0022-3573
DOI - 10.1211/jpp.62.03.0016
Subject(s) - doramectin , rhodamine 123 , p glycoprotein , multiple drug resistance , pharmacology , mtt assay , efflux , flow cytometry , in vitro , intracellular , biology , fluorescein isothiocyanate , drug resistance , chemistry , microbiology and biotechnology , biochemistry , physics , quantum mechanics , fluorescence , zoology , ivermectin
Objectives Multidrug resistance (MDR) is a serious obstacle encountered in cancer treatment. This study was performed to explore the reversal of MDR by doramectin from the avermectin family and nemadectin belonging to the milbemycin family. Methods The MTT assay was used to evaluate the abilities of the two compounds to reverse drug resistance in adriamycin‐resistant human breast carcinoma cells (MCF‐7/adr). Intracellular accumulation of adriamycin was determined by HPLC. The effects of the two compounds on inhibiting P‐glycoprotein (P‐gp) efflux was demonstrated by accumulation of rhodamine 123 in MCF‐7/adr cells. To investigate the mechanism of reversal by the two compounds, the expressions of P‐gp and the MDR1 gene encoding P‐gp were tested by flow cytometry and reverse‐transcriptase PCR. Key findings Doramectin and nemadectin at the high dose of 8 μmol/l significantly increased the sensitivity of MCF‐7/adr cells to adriamycin by 49.35‐ and 23.97‐fold, respectively. They also increased the intracellular accumulation of adriamycin and rhodamine 123 in MCF‐7/adr cells in a dose‐dependent manner. Expression of both P‐gp and MDR1 were down‐regulated. Conclusions Doramectin and nemadectin are promising agents for overcoming MDR in cancer therapy. Doramectin was more potent in reversing MDR.