TY - JOUR
T1 - Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport
AU - Takara, Kohji
AU - Sakaeda, Toshiyuki
AU - Kakumoto, Mikio
AU - Tanigawara, Yusuke
AU - Kobayashi, Hironao
AU - Okumura, Katsuhiko
AU - Ohnishi, Noriaki
AU - Yokoyama, Teruyoshi
PY - 2009
Y1 - 2009
N2 - The purpose of this study is to examine the effects of doxazosin, an α-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 Hvr100-6, 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 Hvr100-6 cells was increased at 3.4- and 17.5-fold, respectively, by the addition of 1 μM doxazosin, whereas prazosin and terazosin had weaker or no such effects. Prazosin at 1 μM 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.
AB - The purpose of this study is to examine the effects of doxazosin, an α-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 Hvr100-6, 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 Hvr100-6 cells was increased at 3.4- and 17.5-fold, respectively, by the addition of 1 μM doxazosin, whereas prazosin and terazosin had weaker or no such effects. Prazosin at 1 μM 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.
KW - Anticancer drug
KW - Digoxin
KW - Doxazosin
KW - MDR1/P-glycoprotein
KW - Multidrug resistance
KW - Reversal
UR - http://www.scopus.com/inward/record.url?scp=70350474281&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70350474281&partnerID=8YFLogxK
U2 - 10.3727/096504009789745601
DO - 10.3727/096504009789745601
M3 - Article
C2 - 19806783
AN - SCOPUS:70350474281
SN - 0965-0407
VL - 17
SP - 527
EP - 533
JO - Oncology research
JF - Oncology research
IS - 11-12
ER -