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

Phytomedicine. 2013 Feb 15;20(3-4):282-94. doi: 10.1016/j.phymed.2012.11.005. Epub 2012 Dec 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • 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


  • 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