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      Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918

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          Abstract

          The acridone carboxamide derivative GG918 (N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide) is a potent inhibitor of MDR1 P-glycoprotein-mediated multidrug resistance. Direct measurements of ATP-dependent MDR1 P-glycoprotein-mediated transport in plasma membrane vesicles from human and rat hepatocyte canalicular membranes indicated 50% inhibition at GG918 concentrations between 8 n M and 80 n M using N-pentyl-[ 3H]quinidinium, [ 14C]doxorubicin and [ 3H]daunorubicin as substrates. The inhibition constant K i for GG918 was 35 n M in rat hepatocyte canalicular membrane vesicles with [ 3H]daunorubicin as the substrate. Photoaffinity labelling of canalicular and recombinant rat Mdr1b P-glycoprotein by [ 3H]azidopine was suppressed by 10 μ M and 40 μ M GG918. The high selectivity of GG918-induced inhibition was demonstrated in canalicular membrane vesicles and by analysis of the hepatobiliary elimination in rats using [ 3H]daunorubicin, [ 3H]taurocholate and [ 3H]cysteinyl leukotrienes as substrates for three distinct ATP-dependent export pumps. Almost complete inhibition of [ 3H]daunorubicin transport was observed at GG918 concentrations that did not affect the other hepatocyte canalicular export pumps. The high potency and selectivity of GG918 for the inhibition of human MDR1 and rat Mdr1b P-glycoprotein may serve to interfere with this type of multidrug resistance and provides a tool for studies on the function of these ATP-dependent transport proteins. © 1999 Cancer Research Campaign

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          Author and article information

          Journal
          Br J Cancer
          British Journal of Cancer
          Nature Publishing Group
          0007-0920
          1532-1827
          March 1999
          : 79
          : 7/8
          : 1053-1060
          Affiliations
          [1 ]Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120, Heidelberg, Germany
          Article
          6690169
          10.1038/sj.bjc.6690169
          2362229
          10098736
          5f1753a2-9295-430e-b80e-7fce559bb313
          Copyright 1999, Cancer Research Campaign
          History
          : 01 June 1998
          : 25 August 1998
          : 26 August 1998
          Categories
          Regular Article

          Oncology & Radiotherapy
          multidrug resistance (mdr),p-glycoprotein,atp-dependent transport,transport inhibition,gg918 (formerly gf120918)

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