Gene expression profiling
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 benzoiciphenanthridine 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. Cheliclonine 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 [micro]g/m1 alkaloid extract and 50 p.M 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.
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Greater celandine; Chelidonium majus L. (Papaveraceae) is a perennial plant native to Europe and Western Asia. In Traditional Chinese Medicine (TCM), it is used against pain, as an antitussive (for bronchitis and whooping cough), anti-inflammatory, and detoxicant. Moreover, in eastern Asia it was valued as a remedy against cancer, jaundice, gout, toothache, and peptic ulcers. European herbal traditions regard greater celandine as a valuable internal remedy to treat appetite loss, stomach cramps, and gastrointestinal problems as well as bile duct and liver disorders (hepatitis, jaundice). Topically, the plant was used against several skin disorders including warts, eczema, and corns (Van Wyk and Wink 2004). At present, the alkaloid extract of C. majus is the major constituents of immunomodulatory preparations and is applied in the therapy of several types of abnormal growths, probably owing to the antimitotic and cytotoxic properties (Gilca et al. 2010). Both crude extracts of C majus and its purified alkaloids exhibit a wide variety of biological activities (anti-inflammatory, immunomodulatory, choleretic, hepatoprotective, analgesic, antitumoral, antimicrobial, and antiviral properties) which can explain the traditional uses of C majus (Gilca et al. 2010). The dried aerial part of C. majus is an official drug in several pharmacopoeias, e.g. in the European Pharmacopoeia (Ph.Eur.5), German Pharmacopoeia (DAB-10), and Hungarian Pharmacopoeia (Ph. Hg. VIII) (Sarkozi et al. 2006). In addition, the alkaloid extract prevents glandular stomach carcinogenesis in rats in vivo treated with N-methyl-N'-nitro-N nitrosoguanidine (MNNG) (Kim et al. 1997).