Characterization of 2-chloro-N10-substituted phenoxazines for reversing multidrug resistance in cancer cells.
Twenty-one 2-chloro-N10-substituted phenoxazines have been synthesized and characterized as potential modulators of multidrug resistance (MDR). Many of the compounds, at a concentration of 100 microM, enhanced accumulation of vinblastine (VLB) in drug-resistant KB8-5 cells to a greater extent than the same concentration of verapamil (VRP). However, the effects on VLB accumulation were specific, because these derivatives had little activity in the parental drug-sensitive line KB3-1. The compounds slowed the efflux of VLB from KB8-5 cells, suggesting that the chlorophenoxazines, like VRP, can inhibit P-glycoprotein (P-gp)-mediated efflux of VLB from this cell line. Two of the chlorophenoxazine derivatives, and also VRP, were able to stimulate the vanadate-sensitive ATPase activity attributable to P-gp in membranes isolated from MDR1 baculovirus-infected Sf9 cells. This result suggests that these modulators exert their effect by directly interacting with P-gp. Apart from the parent unsubstituted molecule, 2-chlorophenoxazine, there was a good correlation between log10P and the ability of the compounds to enhance VLB accumulation in KB8-5. This suggests that lipophilicity of a modulator is important, but is not the sole determinant of potency. Within this series of compounds, the optimal structural features for MDR modulation include a hydrophobic phenoxazine ring with a -Cl atom in the C-2 position and a tertiary amine group four carbons from the tricyclic ring. Many of the agents at the IC10 concentration completely reversed the 37-fold VLB resistance in KB8-5 cells. The most active agents in KB8-5 were able to partially reverse VLB resistance in an MDR colon carcinoma cell line GC3/c1 and completely reversed the 86-fold VLB resistance in the MDR1-overexpressing breast carcinoma cell line BC19/3. These same agents could only partially sensitize BC19/3 cells to taxol and doxorubicin, suggesting that the chlorophenoxazine derivatives show some specificity for modulating VLB resistance.
Thimmaiah
K N
KN
Department of Studies in Chemistry, University of Mysore, India.
Jayashree
B S
BS
Germain
G S
GS
Houghton
P J
PJ
Horton
J K
JK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000230:Adenocarcinoma; D000251:Adenosine Triphosphatases / Q000378:metabolism; D002713:Chlorine; D002999:Clone Cells; D003078:Colchicine / Q000494:pharmacology; D003110:Colonic Neoplasms; D018432:Drug Resistance, Multiple; D006801:Humans; D007624:KB Cells; D015394:Molecular Structure; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000633:toxicity; D012044:Regression Analysis; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000493:pharmacokinetics* / Q000633:toxicity
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D010078:Oxazines; D002713:Chlorine; D014747:Vinblastine; D000251:Adenosine Triphosphatases; D017239:Paclitaxel; D003078:Colchicine