Inhibition of P-glycoprotein transport function and reversion of MDR1 multidrug resistance by cnidiadin.
OBJECTIVE
Overexpression of P-glycoprotein (Pgp) encoded by the MDR1 gene is one of the major obstacles to successful cancer chemotherapy. The goal of this study was to evaluate if, among other natural coumarins, cnidiadin, a furanocoumarin present in traditional Chinese medications and in a spice commonly used in Greek food, inhibits Pgp transport activity and has the potential to reverse MDR1 multidrug resistance.


METHODS
Using MDR1-transfected Madin-Darby canine kidney (MDCK-MDR1) cells as a model of cells expressing the human MDR1 phenotype, and verapamil or CsA or both as positive control, we tested the capacity of six natural coumarins (umbelliferone, esculin, esculetin, cnidiadin, angelicin and psoralen) to induce the accumulation of rhodamine-123 (R-123) and [3H]-vinblastine ([3H]-VBL) and to modulate the photolabeling of Pgp by SDZ 212-122, a diazirin cyclosporin A. The growth-inhibitory effect of cnidiadin and its capacity to enhance the cell toxicity of vinblastine (VBL) or vincristine (VCR) was then evaluated by the WST-1 assay in two cell lines overexpressing Pgp (MDCK-MDR1 and vincristine-resistant KB/VCR).


RESULTS
Cnidiadin was the only tested coumarin capable of significantly accumulating R-123 and [3H]-VBL and inhibiting Pgp photolabeling in MDCK-MDR1 cells. The dose-dependent increase in [3H]-VBL uptake (IC50 26.5 microM) induced by cnidiadin in the dose range 1-100 microM correlated with inhibition of Pgp photolabeling. At 10 microM cnidiadin inhibited photolabeling by 59% and sensitized both MDCK-MDR1 and KB/VCR cells to vinca alkaloids.


CONCLUSIONS
Cnidiadin is a cytotoxic agent capable in vitro of competitively inhibiting the binding and efflux of drug by Pgp and of enhancing the cell toxicity of vinca alkaloids in two cell lines (MDCK-MDR1 and mutant human carcinoma KB/VCR) overexpressing Pgp. This suggests that diet or traditional preparation containing cnidiadin may contribute to the reversal of MDR1 multidrug resistance and may affect the bioavailability of Pgp substrates orally administered. However, due to its cell toxicity, clinical interest in cnidiadin as a chemosensitizer appears to be limited.
Barthomeuf
Chantal
C
UMR-INSERM U-484, Laboratoire de Pharmacognosie et Biotechnologies, Faculté de Pharmacie, Université d'Auvergne, Place H. Dunant, 63001 Clermont-Fd Cedex, France. chantal.barthomeuf@clermont1.fr
Grassi
Jérôme
J
Demeule
Michel
M
Fournier
Chantal
C
Boivin
Dominique
D
Béliveau
Richard
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001682:Biological Availability; D003374:Coumarins / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D011564:Furocoumarins / Q000494:pharmacology*; D019450:Genes, MDR; D014747:Vinblastine / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D011564:Furocoumarins; C502467:cnidiadin; D014750:Vincristine; D014747:Vinblastine