Direct interaction between a quinoline derivative, MS-209, and multidrug resistance protein (MRP) in human gastric cancer cells.
MS-209 is a novel quinoline derivative reversing P-glycoprotein-mediated multidrug resistance (MDR). We investigated the interaction between MS-209 and multidrug resistance protein (MRP) in MRP-overexpressing human gastric cancer cells. We measured [3H]leukotriene C4 uptake into the membrane vesicles of the cells and intracellular calcein and [3H]vincristine accumulation with or without MS-209. In multi-drug-resistant MKN45R0.8 cells selected by doxorubicin, MS-209 dose dependently reduced MRP-mediated [3H]leukotriene C4 uptake and increased calcein accumulation. In both resistant and unselected cell lines expressing the MRP gene, MS-209 increased [3H]vincristine accumulation in proportion with the level of MRP mRNA expression and enhanced the cytotoxicity of etoposide, doxorubicin, and vincristine. The reversal effects correlated with the level of MRP mRNA expression in these cells. Our results indicate that MS-209 effectively reverses intrinsic and acquired MRP-mediated MDR of gastric cancer cells by interacting directly with MRP.
Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, 852-8501, Japan.
T
T
Nakamura
M
M
Oka
K
K
Aizawa
H
H
Soda
M
M
Fukuda
K
K
Terashi
K
K
Ikeda
Y
Y
Mizuta
Y
Y
Noguchi
Y
Y
Kimura
T
T
Tsuruo
S
S
Kohno
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics; D005047:Etoposide / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D017997:Leukotriene C4 / Q000493:pharmacokinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology; D011804:Quinolines / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D013274:Stomach Neoplasms / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D004317:Doxorubicin; D005047:Etoposide; D005452:Fluoresceins; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011339:Probenecid; D011804:Quinolines; D012333:RNA, Messenger; D014750:Vincristine; C087719:dofequidar; C007740:fluorexon