Effects of alpha-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport.
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.
Takara
Kohji
K
Frontier Education Center, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. takara@gm.himeji-du.ac.jp
Sakaeda
Toshiyuki
T
Kakumoto
Mikio
M
Tanigawara
Yusuke
Y
Kobayashi
Hironao
H
Okumura
Katsuhiko
K
Ohnishi
Noriaki
N
Yokoyama
Teruyoshi
T
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics; D004077:Digoxin / Q000493:pharmacokinetics; D017292:Doxazosin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology; D011224:Prazosin / Q000031:analogs & derivatives / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics
C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000317:Adrenergic alpha-Antagonists; D009363:Neoplasm Proteins; D014747:Vinblastine; D004077:Digoxin; C041226:Terazosin; D017292:Doxazosin; D011224:Prazosin; D003630:Daunorubicin