title: Effect of newly synthesized indole derivatives on multidrug resistance in human cancer cells.
abstract: Twenty indole derivatives were investigated for their ability to reverse multidrug resistance (MDR), for their ability to compete with [3H]azidopine in binding to P-glycoprotein (P-gp) and for their hydrophobicity. Six derivatives almost completely reversed the resistance to vincristine (VCR) in multidrug-resistant KB-C2 cells, and other derivatives partially overcame the resistance. The ability of the derivatives to enhance vincristine cytotoxicity did not significantly correlate with the inhibition of [3H]azidopine binding to P-gp or with their hydrophobicity. However, all the derivatives that inhibited > 50% of the photolabeling completely reversed VCR resistance. The 2-pyridyl group with a basic nitrogen atom attached at position 3 of indole in an appropriate spatial orientation seems to be an important feature for the interaction of the indole derivatives with P-gp. One of the derivatives, 1, which has low cytotoxicity and hydrophobicity, completely reversed the resistance of KB-C2 cells to Adriamycin, actinomycin D and VCR. Our data indicate that MDR-reversing indole derivatives with low cytotoxicity and hydrophobicity exist. These characteristics will surely be profitable for clinical use.
authors.affiliation: Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Matsumoto
authors.forename: R
authors.initials: R
authors.lastname: Fujii
authors.forename: M
authors.initials: M
authors.lastname: Sugita
authors.forename: T
authors.initials: T
authors.lastname: Sumizawa
authors.forename: S
authors.initials: S
authors.lastname: Sakai
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: N
authors.initials: N
authors.lastname: Sueda
authors.forename: T
authors.initials: T
authors.lastname: Furukawa
authors.forename: S
authors.initials: S
authors.lastname: Akiyama
authors.forename: Y
authors.initials: Y
authors.lastname: Nagata
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001386:Azides / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007624:KB Cells / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001386:Azides; D002352:Carrier Proteins; D004095:Dihydropyridines; D007211:Indoles; D008562:Membrane Glycoproteins; D014750:Vincristine; C041130:azidopine