Subcellular Distribution of Epothilones in Human Tumor Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2001 Sep 20

PMID 11562452

Citations 6

Authors

R B Lichtner

A Rotgeri

T Bunte

B Buchmann

J Hoffmann

W Schwede

W Skuballa

U Klar

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Evaluation of activity and combination strategies with the microtubule-targeting drug sagopilone in breast cancer cell lines.

Eschenbrenner J, Winsel S, Hammer S, Sommer A, Mittelstaedt K, Drosch M Front Oncol. 2012; 1:44.

PMID: 22649765 PMC: 3355879. DOI: 10.3389/fonc.2011.00044.

Radiosensitizing effect of epothilone B on human epithelial cancer cells.

Baumgart T, Klautke G, Kriesen S, Kuznetsov S, Weiss D, Fietkau R Strahlenther Onkol. 2012; 188(2):177-84.

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The subcellular distribution of small molecules: a meta-analysis.

Zheng N, Tsai H, Zhang X, Shedden K, Rosania G Mol Pharm. 2011; 8(5):1611-8.

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Molecular mode of action and role of TP53 in the sensitivity to the novel epothilone sagopilone (ZK-EPO) in A549 non-small cell lung cancer cells.

Winsel S, Sommer A, Eschenbrenner J, Mittelstaedt K, Klar U, Hammer S PLoS One. 2011; 6(4):e19273.

PMID: 21559393 PMC: 3084814. DOI: 10.1371/journal.pone.0019273.

Diversity through semisynthesis: the chemistry and biological activity of semisynthetic epothilone derivatives.

Altmann K, Gaugaz F, Schiess R Mol Divers. 2011; 15(2):383-99.

PMID: 21197573 DOI: 10.1007/s11030-010-9291-0.

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