School of Life Science, Northeast Agricultural University, Harbin, China.
J Pharm Pharmacol. 2010 Mar;62(3):393-9. doi: 10.1211/jpp.62.03.0016.
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.
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.
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.
Doramectin and nemadectin are promising agents for overcoming MDR in cancer therapy. Doramectin was more potent in reversing MDR.
多药耐药（MDR）是癌症治疗中遇到的严重障碍。本研究旨在探讨阿维菌素家族的多拉菌素和米尔贝肟家族的内马菌素逆转多药耐药的作用。
采用 MTT 法评价两种化合物在阿霉素耐药人乳腺癌细胞（MCF-7/adr）中逆转耐药的能力。采用 HPLC 测定阿霉素的细胞内蓄积。通过 MCF-7/adr 细胞中罗丹明 123 的蓄积来证明两种化合物对抑制 P 糖蛋白（P-gp）外排的作用。为探讨两种化合物逆转耐药的机制，采用流式细胞术和逆转录 PCR 检测 P-gp 和编码 P-gp 的 MDR1 基因的表达。
多拉菌素和内马菌素在 8umol/l 的高剂量下，分别使 MCF-7/adr 细胞对阿霉素的敏感性显著增加 49.35 倍和 23.97 倍。它们还呈剂量依赖性增加 MCF-7/adr 细胞内阿霉素和罗丹明 123 的蓄积。P-gp 和 MDR1 的表达均下调。
多拉菌素和内马菌素是克服癌症治疗中多药耐药的有前途的药物。多拉菌素在逆转多药耐药方面更有效。
