Subcellular distribution of epothilones in human tumor cells.
Epothilones are a new class of natural and potent antineoplastic agents that stabilize microtubules. Although 12,13-epoxide derivatives are potent antiproliferative agents, the activities of the corresponding 12,13-olefin analogs are significantly decreased. These data were confirmed for two new analogs, 6-propyl-EpoB (pEB) and 6-propyl-EpoD (pED), in comparison with the natural compounds EpoB/EpoD, by using human A431, MCF7, and MDR1-overexpressing NCI/Adr cells. By using tritiated pEB/pED, compound uptake, release, and nuclear accumulation were investigated in A431 and NCI/Adr cells. In these cells, epothilones can principally be recognized and exported by Verapamil-sensitive efflux pumps, which are not identical to MDR1. The degree of export depends on the structure, olefin vs. epoxide-analog, and also on the intracellular drug concentration. The accumulation of pED used at 3.5 or 70 nM, respectively, was increased in the presence of 10 microM Verapamil in both cell lines 2- to 8-fold. In contrast, the intracellular levels of pEB were affected by Verapamil only at 3.5 nM pEB in NCI/Adr (2-fold) and not in A431 cells. In addition, strong nuclear accumulation was observed for pEB (40-50%) but not paclitaxel or pED (5-15%) in both cell lines. Our study suggests that differences in growth inhibitory efficacy between epoxide and olefin analogs may be based on different mechanisms of drug accumulation and subcellular distribution.
Lichtner
R B
RB
Research Laboratories of Schering AG, Müllerstrasse 178, 13342 Berlin, Germany. Rosemarie.Lichtner@metagen.de
Rotgeri
A
A
Bunte
T
T
Buchmann
B
B
Hoffmann
J
J
Schwede
W
W
Skuballa
W
W
Klar
U
U
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D034261:Epothilones; D004852:Epoxy Compounds / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D018942:Macrolides / Q000493:pharmacokinetics* / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D034261:Epothilones; D004852:Epoxy Compounds; D018942:Macrolides; D013844:Thiazoles; C121425:epothilone E; C093787:epothilone A; D014700:Verapamil; D017239:Paclitaxel; C114026:desoxyepothilone B; C093788:epothilone B