Effects of alpha-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport.

Article Details

Citation

Takara K, Sakaeda T, Kakumoto M, Tanigawara Y, Kobayashi H, Okumura K, Ohnishi N, Yokoyama T

Effects of alpha-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport.

Oncol Res. 2009;17(11-12):527-33.

PubMed ID
19806783 [ View in PubMed
]
Abstract

The purpose of this study is to examine the effects of doxazosin, an alpha-adrenoceptor antagonist, on P-glycoprotein/MDR1-mediated multidrug resistance (MDR) and the transport of anticancer drugs. The effects of doxazosin, prazosin, and terazosin on MDR1-mediated MDR were assessed in human cervical carcinoma HeLa cells and the MDR1-overexpressing derivative Hvrl00-6, established by stepwise increases of the vinblastine concentration in the culture medium. The effects of doxazosin on the transcellular transport and intracellular accumulation of [3H]vinblastine, [3H]daunorubicin, and [3H]digoxin, all MDR1 substrates, were evaluated using LLC-GA5-COL150 cell monolayers, established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK1 cells. The sensitivity to vinblastine and paclitaxel of Hvrl00-6 cells was increased at 3.4- and 17.5-fold, respectively, by the addition of 1 microM doxazosin, whereas prazosin and terazosin had weaker or no such effects. Prazosin at 1 microM had a reversal effect on the sensitivity to vinblastine, whereas terazosin had no effect. In transport experiments, doxazosin concentration dependently increased the apical-to-basal transport of radiolabeled drugs in LLC-GA5-COL150 cells, but did not show remarkable effects on the basal-to-apical transport. In addition, doxazosin restored the intracellular accumulation in a concentration-dependent manner in LLC-GA5-COL150 cells. Doxazosin may partly reverse MDR by inhibiting MDR1-mediated transport, making it a candidate lead compound in the development of a reversing agent for MDR.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
DaunorubicinP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
DigoxinP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
DoxazosinP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
PrazosinP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Modulator
Details
TerazosinP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
VinblastineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details