title: ABCG2 confers resistance to indolocarbazole compounds by ATP-dependent transport.
abstract: The ABC half-transporter, ABCG2, is known to confer resistance to chemotherapeutic agents including indolocarbazole derivatives. MCF7 cells were introduced by either wild type ABCG2 (ABCG2-482R) or mutant ABCG2 (-482T), whose amino acid at position 482 is substituted to threonine from arginine, and their cross-resistance pattern was analyzed. Although this amino acid substitution seems to affect cross-resistance patterns, both 482T- and 482R-transfectants showed strong resistance to indolocarbazoles, confirming that ABCG2 confers resistance to them. For further characterization of ABCG2-mediated transport, we investigated indolocarbazole compound A (Fig. 1) excretion in cell-free system. Compound A was actively transported in membrane vesicles prepared from one of the 482T- transfectants and its uptake was supported by hydrolysis of various nucleoside triphosphates. This transport was inhibited completely by the other indolocarbazole compound, but not by mitoxantrone, implying that the binding site of mitoxantrone or the transport mechanisms for mitoxantrone is different from those of indolocarbazoles. These results showed that ABCG2 confers resistance to indolocarbazoles by transporting them in an energy-dependent manner.
authors.affiliation: Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories, 3 Okubo, Ibaraki 300-2611, Japan.
authors.forename: Rinako
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hara
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Arakawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Nishimura
authors.forename: Hideya
authors.initials: H
authors.lastname: Komatani
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology*; D001943:Breast Neoplasms / Q000378:metabolism; D002227:Carbazoles / Q000378:metabolism*; D002474:Cell-Free System; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000378:metabolism*; D008942:Mitoxantrone / Q000378:metabolism; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009994:Osmolar Concentration; D014407:Tumor Cells, Cultured
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002227:Carbazoles; D007211:Indoles; D009363:Neoplasm Proteins; D000255:Adenosine Triphosphate; D008942:Mitoxantrone