Pharmacological characterization of N-substituted phenoxazines directed toward reversing Vinca alkaloid resistance in multidrug-resistant cancer cells.
Previously we reported the synthesis and partial characterization of 21 N10-substituted phenoxazines in reversing Vinca alkaloid resistance. Here we report on a subset of these compounds; we have compared their activities in increasing Vinca alkaloid accumulation and reversing drug resistance in KB-ChR8-5 and GC3/c1 (human colon carcinoma) cell lines. Results demonstrated that 1) N-substituted phenoxazines increase accumulation of vinblastine; 2) within this series, there is little correlation or ranking of activity between the two cell lines when Vinca alkaloid accumulation is compared at equal concentrations of modulator; 3) N-substituted phenoxazines demonstrate both quantitative and qualitative differences, compared with verapamil, a standard modulator; and 4) the series includes at least two compounds, 10-[3'-[N-bis(hydroxyethyl)amino]propyl]phenoxazine and 10-(N-piperidinoacetyl)phenoxazine, which increase Vinca alkaloid accumulation but do not significantly inhibit efflux. Additionally, certain of these multidrug resistance modulators significantly enhance accumulation (8-50-fold) of Vinca alkaloids in cell lines with very low or undetectable P-glycoprotein levels, where verapamil has little activity. It is concluded that at least part of the activity of some of these N-substituted phenoxazine modulators may be mediated through a P-glycoprotein-independent mechanism.
Horton
J K
JK
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Thimmaiah
K N
KN
Harwood
F C
FC
Kuttesch
J F
JF
Houghton
P J
PJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001386:Azides / Q000378:metabolism; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004095:Dihydropyridines / Q000378:metabolism; D004347:Drug Interactions; D004351:Drug Resistance; D006801:Humans; D007624:KB Cells; D008562:Membrane Glycoproteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000378:metabolism; D014748:Vinca Alkaloids / Q000378:metabolism / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001386:Azides; D002352:Carrier Proteins; D004095:Dihydropyridines; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D010078:Oxazines; D014748:Vinca Alkaloids; C041130:azidopine; C039203:phenoxazine