Modulation of multidrug resistance in cancer cells by chelidonine and Chelidonium majus alkaloids.

Abstract

Cancer cells often develop multidrug resistance (MDR) which is a multidimensional problem involving several mechanisms and targets. This study demonstrates that chelidonine and an alkaloid extract from Chelidonium majus, which contains protoberberine and benzo[c]phenanthridine alkaloids, has the ability to overcome MDR of different cancer cell lines through interaction with ABC-transporters, CYP3A4 and GST, by induction of apoptosis, and cytotoxic effects. Chelidonine and the alkaloid extract inhibited P-gp/MDR1 activity in a concentration-dependent manner in Caco-2 and CEM/ADR5000 and reversed their doxorubicin resistance. In addition, chelidonine and the alkaloid extract inhibited the activity of the drug modifying enzymes CYP3A4 and GST in a dose-dependent manner. The alkaloids induced apoptosis in MDR cells which was accompanied by an activation of caspase-3, -8,-6/9, and phosphatidyl serine (PS) exposure. cDNA arrays were applied to identify differentially expressed genes after treatment with chelidonine and the alkaloid extract. The expression analysis identified a common set of regulated genes related to apoptosis, cell cycle, and drug metabolism. Treatment of Caco-2 cells with 50 μg/ml alkaloid extract and 50 μM chelidonine for up to 48 h resulted in a significant decrease in mRNA levels of P-gp/MDR1, MRP1, BCRP, CYP3A4, GST, and hPXR and in a significant increase in caspase-3 and caspase-8 mRNA. Thus, chelidonine is a promising model compound for overcoming MDR and for enhancing cytotoxicity of chemotherapeutics, especially against leukaemia cells. Its efficacy needs to be confirmed in animal models.

• Authors: Mahmoud Zaki El-Readi, SafaaYehia Eid, Mohamed Lotfy Ashour, Ahmad Tahrani, Michael Wink
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 20 Issue 3-4 Pg. 282-94 (Feb 15 2013) ISSN: 1618-095X [Electronic] Germany
• PMID: 23238299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: Crown Copyright © 2012. Published by Elsevier GmbH. All rights reserved.

Chemical References

• ATP-Binding Cassette Transporters
• Alkaloids
• Antibiotics, Antineoplastic
• Benzophenanthridines
• Cytochrome P-450 CYP3A Inhibitors
• Drugs, Chinese Herbal
• Plant Extracts
• Doxorubicin
• chelidonine
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Glutathione Transferase
• Caspases

Topics

• ATP-Binding Cassette Transporters (antagonists & inhibitors)
• Alkaloids (chemistry)
• Antibiotics, Antineoplastic
• Apoptosis (drug effects)
• Benzophenanthridines (pharmacology)
• Caspases (metabolism)
• Cell Line, Tumor
• Chelidonium (chemistry)
• Chromatography, Liquid
• Cytochrome P-450 CYP3A
• Cytochrome P-450 CYP3A Inhibitors
• Doxorubicin
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Drug Synergism
• Drugs, Chinese Herbal (pharmacology)
• Enzyme Activation (drug effects)
• Gene Expression Profiling
• Glutathione Transferase (antagonists & inhibitors)
• Humans
• Mass Spectrometry
• Oligonucleotide Array Sequence Analysis
• Plant Extracts (chemistry)
• Real-Time Polymerase Chain Reaction