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

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.

• Authors: Aili Gao, Xiangjing Wang, Wensheng Xiang, Hongsheng Liang, Jiguo Gao, Yijun Yan
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 62 Issue 3 Pg. 393-9 (Mar 2010) ISSN: 2042-7158 [Electronic] England
• PMID: 20487225 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antibiotics, Antineoplastic
• Macrolides
• RNA, Messenger
• Rhodamine 123
• nemadectin
• Ivermectin
• Doxorubicin
• doramectin

Topics

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Absorption (drug effects)
• Antibiotics, Antineoplastic (pharmacokinetics, pharmacology)
• Breast Neoplasms (drug therapy, metabolism)
• Carcinoma (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Doxorubicin (pharmacokinetics)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, MDR
• Humans
• Inhibitory Concentration 50
• Ivermectin (analogs & derivatives, pharmacology)
• Macrolides (pharmacology)
• RNA, Messenger (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Rhodamine 123 (pharmacokinetics)