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  • Title: Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin.
    Author: Gao A, Wang X, Xiang W, Liang H, Gao J, Yan Y.
    Journal: J Pharm Pharmacol; 2010 Mar; 62(3):393-9. PubMed ID: 20487225.
    Abstract:
    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 mumol/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.
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