Abstract | PURPOSE: 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: 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. CONCLUSION:
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.
|
Authors | Chantal Barthomeuf, Jérôme Grassi, Michel Demeule, Chantal Fournier, Dominique Boivin, Richard Béliveau |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 56
Issue 2
Pg. 173-81
(Aug 2005)
ISSN: 0344-5704 [Print] Germany |
PMID | 15824923
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
- Antineoplastic Agents, Phytogenic
- Coumarins
- Furocoumarins
- cnidiadin
- Vincristine
- Vinblastine
|
Topics |
- ATP Binding Cassette Transporter, Subfamily B, Member 1
(biosynthesis, genetics, physiology)
- Administration, Oral
- Animals
- Antineoplastic Agents, Phytogenic
(pharmacology)
- Biological Availability
- Coumarins
(pharmacology)
- Dogs
- Drug Interactions
- Drug Resistance, Multiple
- Furocoumarins
(pharmacology)
- Genes, MDR
- Vinblastine
(pharmacology)
- Vincristine
(pharmacology)
|