Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein.
Indomethacin-mediated reversal of multidrug resistance and drug efflux in human and murine cell lines overexpressing MRP, but not P-glycoprotein.
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DOI：
10.1038/bjc.1997.145
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发表时间：
1997
影响因子：
8.8
通讯作者：
Levy, SB
中科院分区：
文献类型：
--
作者：
Draper, MP;Martell, RL;Levy, SB
荧光染料BCECF[2', 7'-双-（2-羧基乙基）-5-(6)-羧基荧光素]的积累减少表征了过表达多药耐药蛋白（MRP）的小鼠和人多药耐药细胞系。吲哚美辛（10微米）是一种已知的环加氧酶和谷胱甘肽s转移酶抑制剂以及阴离子转运调节剂，可增加表达mrp的小鼠和人细胞中BCECF的积累并阻断其外排。该药不影响p -糖蛋白（P-gp）介导的罗丹明123的输出。吲哚美辛对BCECF外排的影响并没有被外源性前列腺素的加入所逆转，这表明该药的作用机制不是减少前列腺素的合成。吲哚美辛还增加了过表达MRP的小鼠和人类细胞系的多药敏感性，但没有增加p- gp相关耐药的细胞系。此外，吲哚美辛调节了MRP细胞中长春新碱积累的减少，而P-gp细胞中则没有。这些数据表明，吲哚美辛是MRP的特异性抑制剂，可能通过抑制谷胱甘肽- s -转移酶起作用，或者在运输部位与药物直接竞争。
Decreased accumulation of the fluorescent dye BCECF [2', 7'-bis-(2-carboxyethyl)-5-(6)- carboxyfluorescein] characterized murine and human multidrug-resistant cell lines overexpressing the multidrug resistance protein (MRP). Indomethacin (10 microM), a known cyclo-oxygenase and glutathione-S-transferase inhibitor as well as a modulator of anion transport, increased accumulation and blocked efflux of BCECF in MRP-expressing murine and human cells. The drug did not affect P-glycoprotein (P-gp)-mediated export of rhodamine 123. The indomethacin effect on BCECF efflux was not reversed by the addition of exogenous prostaglandins, suggesting that the drug acts by a mechanism other than decreasing prostaglandin synthesis. Indomethacin also increased multidrug susceptibility of both murine and human cell lines overexpressing MRP, but not those displaying P-gp-associated resistance. In addition, indomethacin modulated the decreased vincristine accumulation in cells expressing MRP, but not in those expressing P-gp. These data suggest that indomethacin is a specific inhibitor of MRP, possibly functioning by inhibition of glutathione-S-transferase or, alternatively, by direct competition with the drug at the transport site.
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DOI：
10.1006/bbrc.1995.1017
发表时间：
1995-01-05
影响因子：
3.1
作者：
GEKELER, V;BOER, R;BECK, J
通讯作者：
BECK, J
影响因子：
5.8
作者：
COLLINGTON, GK;ALLEN, CN;HIRST, BH
通讯作者：
HIRST, BH
影响因子：
3.5
作者：
FELLER, N;BROXTERMAN, HJ;PINEDO, HM
通讯作者：
PINEDO, HM
DOI：
10.1073/pnas.91.19.8822
发表时间：
1994-09-13
影响因子：
11.1
作者：
ZAMAN, GJR;FLENS, MJ;BORST, P
通讯作者：
BORST, P
影响因子：
5.8
作者：
COLLINGTON, GK;HUNTER, J;HIRST, BH
通讯作者：
HIRST, BH