Reversal of P-glycoprotein-mediated multidrug resistance in vitro by milbemycin compounds in adriamycin-resistant human breast carcinoma (MCF-7/adr) cells.
The effects of milbemycin A(4) (MB A(4)), milbemycin oxime A(4) (MBO A(4)) and milbemycin beta(1) (MB beta(1)) on reversing multidrug resistance (MDR) of tumor cells were firstly conducted according to the following research, including MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay, the accumulation of adriamycin, the accumulation and efflux of rhodamine 123 (Rh123), the regulations of MDR1 gene, and expression of P-gp. The three milbemycins (5muM) showed strong potency to increase adriamycin cytotoxicity toward adriamycin-resistant human breast carcinoma cells MCF-7/adr with reversal fold (RF) of 21.42, 19.06 and 14.89, respectively. In addition, the mechanisms of milbemycins on P-glycoprotein (P-gp)-mediated MDR demonstrated that the milbemycins significantly increased the intracellular accumulations of adriamycin and Rh123 via inhibiting P-gp transport function. Based on the analysis of the P-gp and MDR1 gene expression using flow cytometry and RT-PCR, the results revealed that milbemycin compounds, particularly MB A(4), could regulate down the expression of the P-gp and MDR1 gene. These findings suggest that the milbemycins probably represent promising agents for overcoming MDR in cancer therapy, and especially MB A(4) is better modulator with the lowest toxicity.
Xiang
Wensheng
W
School of Life Science, Northeast Agricultural University, Xiangfang District, Harbin, China.
Gao
Aili
A
Liang
Hongsheng
H
Li
Changyu
C
Gao
Jiguo
J
Wang
Qing
Q
Shuang
Bao
B
Zhang
Ji
J
Yan
Yijun
Y
Wang
Xiangjing
X
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018942:Macrolides / Q000378:metabolism / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D005456:Fluorescent Dyes; D018942:Macrolides; C078973:milbemycin oxime; D020112:Rhodamine 123; D004317:Doxorubicin; C027837:moxidectin