Abstract
The cytotoxicity of the alkaloid emetine was determined in six human cell lines that
differ in the expression of ABC transporters, such as multiple drug resistance protein
1 (MDR1/ABCB1) and multidrug resistance associated protein 1 (MRP1/ABCC1). Emetine
reveals a substantial cytotoxicity due to apoptosis that is inversely correlated with
the expression of MDR1. Confluent Caco-2 cells with high MDR1 activity and the MDR1
over-expressing leukemia cell line CEM/ADR5000 are more resistant towards emetine
(EC50 250 μM and 2 μM, respectively) than cells with a low expression of MDR1 (Jurkat cells,
CCRF-CEM cells, HL-60 cells) or cells which over-express MRP1 (HL-60/AR) (EC50 between 0.05 μM for CCRF-CEM and 0.17 μM for Jurkat cells). Apparently emetine is
a substrate for MDR1 but not for MRP1. Furthermore, emetine is able to up-regulate
the expression of MDR1 as shown in vitro by real-time PCR and transport activity studies.
Key words
Emetine - cytotoxicity - ABC-transporter - P-glycoprotein - MDR1 - MRP1
References
- 1 Wyk B -Ev, Wink M. Medicinal plants of the world. Pretoria; Briza 2004
- 2
Bell D R.
Treatment of amoebiasis.
Trop Doct.
1973;
3
140-3
- 3
Grollman A P.
Structural basis for inhibition of protein synthesis by emetine and cycloheximide
based on an analogy between Ipecac alkaloids and glutarimide antibiotics.
Proc Natl Acad Sci USA.
1966;
56
1867-74
- 4
Gupta R S, Siminovitch L.
The isolation and preliminary characterization of somatic cell mutants resistant to
the protein synthesis inhibitor-emetine.
Cell.
1976;
9
213-9
- 5
Grollman A P, Huang M T.
Inhibitors of protein synthesis in eukaryotes: tools in cell research.
Fed Proc.
1673;
32
1673-8
- 6
Pestka S.
Inhibitors of ribosome functions.
Annu Rev Microbiol.
1971;
25
487-562
- 7
Watanabe N, Shimada H.
Effects of emetine on initiation of DNA synthesis in embryonic cells of sea urchin.
Cell Differ.
1983;
13
239-45
- 8
Wink M, Schmeller T, Latz-Brüning B.
Modes of action of allelochemical alkaloids: interaction with neuroreceptors, DNA,
and other molecular targets.
J Chem Ecol.
1998;
24
1881-937
- 9
Wink M.
Evolution of secondary metabolites from an ecological and molecular phylogenetic perspective.
Phytochemistry.
2003;
64
3-19
- 10 Stuffness M, Douros J D. Miscellaneous natural products with antitumor activity. In:
Cassady JM, Douros JD, editors
Anticancer agents based on natural product models. New York; Academic Press 1980: p 469-70
- 11
Kochi S K, Collier R J.
DNA fragmentation and cytolysis in U937 cells treated with diphtheria toxin or other
inhibitors of protein synthesis.
Exp Cell Res.
1993;
208
296-302
- 12
Bicknell G R, Snowden R T, Cohen G M.
Formation of high molecular mass DNA fragments is a marker of apoptosis in the human
leukaemic cell line, U937.
J Cell Sci.
1994;
107
2483-9
- 13
Watanabe N, Iwamoto T, Dickinson D A, Iles K E, Forman H J.
Activation of the mitochondrial caspase cascade in the absence of protein synthesis
does not require c-Jun N-terminal kinase.
Arch Biochem Biophys.
2002;
405
231-40
- 14
Samuelson J, Ayala P, Orozco E, Wirth D.
Emetine-resistant mutants of Entamoeba histolytica overexpress mRNAs for multidrug resistance.
Mol Biochem Parasitol.
1990;
38
281-90
- 15
Borgnia M J, Eytan G D, Assaraf Y G.
Competition of hydrophobic peptides, cytotoxic drugs, and chemosensitizers on a common
P-glycoprotein pharmacophore as revealed by its ATPase activity.
J Biol Chem.
1996;
271
3163-71
- 16
Wang E, Lew K, Barecki M, Casciano C N, Clement R P, Johnson W W.
Quantitative distinctions of active site molecular recognition by P-glycoprotein and
cytochrome P450 3A4.
Chem Res Toxicol.
2001;
14
1596-603
- 17
Gant T W, Silverman J A, Thorgeirsson S S.
Regulation of P-glycoprotein gene expression in hepatocyte cultures and liver cell
lines by a trans-acting transcriptional repressor.
Nucleic Acids Res.
1992;
20
2841-6
- 18
Borenfreund E, Babich H, Martin-Alguacil N.
Rapid chemosensitivity assay with human normal and tumor cells in vitro
.
In Vitro Cell Dev Biol.
1990;
26
1030-4
- 19
Mosmann T.
Rapid colorimetric assay for cellular growth and survival: application to proliferation
and cytotoxicity assays.
J Immunol Methods.
1983;
65
55-63
- 20
Nicoletti I, Migliorati G, Pagliacci M C, Grignani F, Riccardi C.
A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining
and flow cytometry.
J Immunol Methods.
1991;
139
271-9
- 21
Ludescher C, Thaler J, Drach D, Drach J, Spitaler M, Gattringer C. et al .
Detection of activity of P-glycoprotein in human tumour samples using rhodamine 123.
Br J Haematol.
1992;
82
161-8
- 22
Albermann N, Schmitz-Winnenthal F H, Z'graggen K, Volk C, Hoffmann M M, Haefeli W E.
et al .
Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2,
and PXR in peripheral blood mononuclear cells and their relationship with the expression
in intestine and liver.
Biochem Pharmacol.
2005;
70
949-58
- 23
Lin H -L, Liu T -Y, Chi C -W, Wu C -W.
Berberine modulates expression of mdr1 gene product and the responses of digestive
track cancer cells to Paclitaxel.
Br J Cancer.
1999;
81
416-22
- 24
Tebbi C K, Chervinsky D, Baker R M.
Modulation of drug resistance in homoharringtonine-resistant C-1300 neuroblastoma
cells with cyclosporine A and dipyridamole.
J Cell Physiol.
1991;
148
464-71
- 25
Hoskins J, DeHerdt S V, Moore R E, Bumol T F.
The development and characterization of Vinca alkaloid-resistant Caco-2 human colorectal
cell lines expressing mdr-1.
Int J Cancer.
1993;
53
680-8
- 26
Michieli M, Damiani D, Geromin A, Michelutti A, Fanin R, Raspadori D. et al .
Overexpression of multidrug resistance-associated p170-glycoprotein in acute non-lymphocytic
leukemia.
Eur J Haematol.
1992;
48
87-92
- 27
Fricker G, Drewe J, Huwyler J, Gutmann H, Beglinger C.
Relevance of p-glycoprotein for the enteral absorption of cyclosporin A: in vitro-in vivo correlation.
Br J Pharmacol.
1996;
118
1841-7
Prof. Dr. Michael Wink
Institute of Pharmacy and Molecular Biotechnology
Department of Biology
University of Heidelberg
Im Neuenheimer Feld 364
69120 Heidelberg
Germany
Phone: +49-6221-54-4880
Fax: +49-6221-54-4884
Email: wink@uni-hd.de