Effect of newly synthesized indole derivatives on multidrug resistance in human cancer cells.
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.
Matsumoto
T
T
Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.
Fujii
R
R
Sugita
M
M
Sumizawa
T
T
Sakai
S
S
Takahashi
T
T
Sueda
N
N
Furukawa
T
T
Akiyama
S
S
Nagata
Y
Y
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
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