Reduction of Cytotoxicity of the Alkaloid Emetine through P-Glycoprotein (MDR1/ABCB1) in Human Caco-2 Cells and Leukemia Cell Lines

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

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