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Inhibition of P-glycoprotein transport function and reversion of MDR1 multidrug resistance by cnidiadin

Chantal Barthomeuf1, Jérôme Grassi, Michel Demeule

  • 1UMR-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

Cancer Chemotherapy and Pharmacology
|April 13, 2005
PubMed
Abstract

Insights

Cnidiadin, a natural coumarin, inhibits P-glycoprotein (Pgp) drug efflux and reverses multidrug resistance in cancer cells. While effective in vitro, its clinical use as a chemosensitizer is limited by cytotoxicity.

Area of Science:

  • Pharmacology
  • Natural Products Chemistry
  • Cancer Biology

Background:

  • P-glycoprotein (Pgp) overexpression, encoded by the MDR1 gene, is a significant barrier in cancer chemotherapy.
  • Natural compounds are being investigated for their potential to overcome multidrug resistance (MDR).

Purpose of the Study:

  • To evaluate cnidiadin, a furanocoumarin, for its ability to inhibit Pgp transport activity.
  • To determine if cnidiadin can reverse MDR1-mediated multidrug resistance.

Main Methods:

  • Utilized MDCK-MDR1 cells, a model for MDR1 phenotype expression.
  • Assessed coumarins' capacity to accumulate rhodamine-123 and [3H]-vinblastine, and modulate Pgp photolabeling.
  • Evaluated cnidiadin's growth-inhibitory and chemosensitizing effects on vinca alkaloids in Pgp-overexpressing cell lines.

Main Results:

  • Cnidiadin was the sole coumarin to significantly accumulate rhodamine-123 and [3H]-vinblastine, and inhibit Pgp photolabeling.
  • Cnidiadin demonstrated dose-dependent inhibition of Pgp photolabeling (IC50 26.5 microM) and increased [3H]-VBL uptake.
  • At 10 microM, cnidiadin inhibited Pgp photolabeling by 59% and sensitized cells to vinca alkaloids.

Conclusions:

  • Cnidiadin competitively inhibits Pgp drug binding and efflux in vitro, enhancing vinca alkaloid cytotoxicity in Pgp-overexpressing cells.
  • Dietary or traditional sources of cnidiadin may influence MDR1 resistance and oral drug bioavailability.
  • Cnidiadin's inherent cytotoxicity limits its clinical application as a chemosensitizer.

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