A leukotriene receptor antagonist, ONO-1078, modulates drug sensitivity and leukotriene C4 efflux in lung cancer cells expressing multidrug resistance protein.
ONO-1078 is a new class of peptide leukotriene receptor antagonist, and multidrug resistance protein (MRP) is a membrane tranporter of multiple anticancer drugs and endogenous leukotriene C4 (LTC4). We investigated the effects of ONO-1078 on drug sensitivity and LTC4-efflux in MRP-expressing lung cancer cells. Drug sensitivity, intracellular vincristine accumulation, and intracellular and extracellular LTC4 concentrations were measured with or without ONO-1078. The effect of ONO-1078 on MRP-mediated calcein-efflux was determined by flow cytometry. ONO-1078 (1 to 10 microM) dose-dependently enhanced the sensitivity of NCI-H520 cells to vincristine with the reduced accumulation, and also enhanced the sensitivity to doxorubicin and etoposide. ONO-1078 inhibited both LTC4- and calcein-efflux from the cells with increased intracellular accumulations. Our findings indicate that ONO-1078 modulates multidrug resistance and inhibits LTC4-efflux in lung cancer cells, by inhibition of MRP function.
Nakano
R
R
Second Department of Internal Medicine, Nagasaki University School of Medicine, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan.
Oka
M
M
Nakamura
T
T
Fukuda
M
M
Kawabata
S
S
Terashi
K
K
Tsukamoto
K
K
Noguchi
Y
Y
Soda
H
H
Kohno
S
S
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000230:Adenocarcinoma / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology*; D017997:Leukotriene C4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D002867:Chromones; D005452:Fluoresceins; D005456:Fluorescent Dyes; D020024:Leukotriene Antagonists; D017997:Leukotriene C4; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014750:Vincristine; C047681:pranlukast; C007740:fluorexon