Reversal of P-glycoprotein-mediated multidrug resistance in vitro by doramectin and nemadectin.
OBJECTIVE
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.


RESULTS
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.
Gao
Aili
A
School of Life Science, Northeast Agricultural University, Harbin, China.
Wang
Xiangjing
X
Xiang
Wensheng
W
Liang
Hongsheng
H
Gao
Jiguo
J
Yan
Yijun
Y
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000042:Absorption / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019450:Genes, MDR; D006801:Humans; D020128:Inhibitory Concentration 50; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020112:Rhodamine 123 / Q000493:pharmacokinetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D018942:Macrolides; D012333:RNA, Messenger; D020112:Rhodamine 123; C056041:nemadectin; D007559:Ivermectin; D004317:Doxorubicin; C084101:doramectin