title: 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.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany. El-Readi@uni-heidelberg.de
authors.forename: Mahmoud Zaki
authors.initials: MZ
authors.lastname: El-Readi
authors.forename: SafaaYehia
authors.initials: S
authors.lastname: Eid
authors.forename: Mohamed Lotfy
authors.initials: ML
authors.lastname: Ashour
authors.forename: Ahmad
authors.initials: A
authors.lastname: Tahrani
authors.forename: Michael
authors.initials: M
authors.lastname: Wink
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000470:Alkaloids / Q000737:chemistry; D000903:Antibiotics, Antineoplastic; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D028281:Chelidonium / Q000737:chemistry*; D002853:Chromatography, Liquid; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004317:Doxorubicin; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D020869:Gene Expression Profiling; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D013058:Mass Spectrometry; D020411:Oligonucleotide Array Sequence Analysis; D010936:Plant Extracts / Q000737:chemistry; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D018528:ATP-Binding Cassette Transporters; D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D053119:Benzophenanthridines; D065692:Cytochrome P-450 CYP3A Inhibitors; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D004317:Doxorubicin; C062047:chelidonine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D005982:Glutathione Transferase; D020169:Caspases