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

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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
DOIs
Publication statusPublished - 2009 Jan 1

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    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, 17(11-12), 527-533. https://doi.org/10.3727/096504009789745601