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

Kohji Takara, Toshiyuki Sakaeda, Mikio Kakumoto, Yusuke Tanigawara, Hironao Kobayashi, Katsuhiko Okumura, Noriaki Ohnishi, Teruyoshi Yokoyama

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)527-533
Number of pages7
JournalOncology Research
Volume17
Issue number11-12
Publication statusPublished - 2009

Fingerprint

Doxazosin
Transcytosis
Multiple Drug Resistance
Terazosin
Adrenergic Receptors
Vinblastine
Prazosin
LLC-PK1 Cells
Daunorubicin
Digoxin
P-Glycoprotein
Paclitaxel
HeLa Cells
Pharmaceutical Preparations
Transfection
Culture Media
Swine
Complementary DNA
Epithelial Cells
Carcinoma

Keywords

  • Anticancer drug
  • Digoxin
  • Doxazosin
  • MDR1/P-glycoprotein
  • Multidrug resistance
  • Reversal

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Takara, K., Sakaeda, T., Kakumoto, M., Tanigawara, Y., Kobayashi, H., Okumura, K., ... Yokoyama, T. (2009). Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport. Oncology Research, 17(11-12), 527-533.

Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport. / Takara, Kohji; Sakaeda, Toshiyuki; Kakumoto, Mikio; Tanigawara, Yusuke; Kobayashi, Hironao; Okumura, Katsuhiko; Ohnishi, Noriaki; Yokoyama, Teruyoshi.

In: Oncology Research, Vol. 17, No. 11-12, 2009, p. 527-533.

Research output: Contribution to journalArticle

Takara, K, Sakaeda, T, Kakumoto, M, Tanigawara, Y, Kobayashi, H, Okumura, K, Ohnishi, N & Yokoyama, T 2009, 'Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport', Oncology Research, vol. 17, no. 11-12, pp. 527-533.
Takara, Kohji ; Sakaeda, Toshiyuki ; Kakumoto, Mikio ; Tanigawara, Yusuke ; Kobayashi, Hironao ; Okumura, Katsuhiko ; Ohnishi, Noriaki ; Yokoyama, Teruyoshi. / Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport. In: Oncology Research. 2009 ; Vol. 17, No. 11-12. pp. 527-533.
@article{36a628e524ad41928f172eca12e27b8d,
title = "Effects of α-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport",
abstract = "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.",
keywords = "Anticancer drug, Digoxin, Doxazosin, MDR1/P-glycoprotein, Multidrug resistance, Reversal",
author = "Kohji Takara and Toshiyuki Sakaeda and Mikio Kakumoto and Yusuke Tanigawara and Hironao Kobayashi and Katsuhiko Okumura and Noriaki Ohnishi and Teruyoshi Yokoyama",
year = "2009",
language = "English",
volume = "17",
pages = "527--533",
journal = "Oncology Research",
issn = "0965-0407",
publisher = "Cognizant Communication Corporation",
number = "11-12",

}

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

M3 - Article

C2 - 19806783

AN - SCOPUS:70350474281

VL - 17

SP - 527

EP - 533

JO - Oncology Research

JF - Oncology Research

SN - 0965-0407

IS - 11-12

ER -