Planta Med 2007; 73(15): 1563-1567
DOI: 10.1055/s-2007-993754
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Reversal of P-Glycoprotein-Mediated Drug Efflux by Eudesmin from Haplophyllum perforatum and Cytotoxicity Pattern versus Diphyllin, Podophyllotoxin and Etoposide

Suzanne Lim1 , 2 , Jérôme Grassi3 , Valentina Akhmedjanova4 , Eric Debiton1 , 2 , Guy Balansard5 , Richard Beliveau3 , Chantal Barthomeuf1 , 2
  • 1INSERM-484, Clermont-Ferrand, France
  • 2Laboratoire de Pharmacognosie et Biotechnologies, Faculté de Pharmacie, Université d’Auvergne, Clermont-Ferrand, France
  • 3Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-UQAM, Montréal, Québec, Canada
  • 4Laboratory of Alkaloids Chemistry, Yunusov Institute of the Chemistry of Plant Substances, Tashkent, Uzbekistan
  • 5Laboratoire de Pharmacognosie et Phytothérapie, Faculté de Pharmacie, Université Aix-Marseille II, Marseille, France
Further Information

Publication History

Received: July 20, 2007 Revised: October 4, 2007

Accepted: October 19, 2007

Publication Date:
11 December 2007 (online)

Abstract

The present study focuses on eudesmin (bicyclic lignan, 0.15 % of dry leaves) and diphyllin (arylnaphthalene lignan, 0.1 % of dry roots), both isolated from H. perforatum Kar. et Kir, a Rutaceae species endemic to Uzbekistan. We first compared their specificity for cancer cells with those of etoposide and podophyllotoxin by screening their cytotoxicity on 3 healthy cell-lines and 7 sensitive or resistant human solid cancer lines. We then tested their capacity to reverse P-glycoprotein-mediated multidrug resistance (MDR) by assaying dye and drug uptake in MDR1-transfected Madin-Darby canine kidney (MDCK-MDR1) and doxorubicine-resistant human breast carcinoma cells (MCF7/Dox). Eudesmin displays IC50 values > 100 μM on all tested lines. Our data provide the first demonstration that this non-toxic lignan reverses Pgp-mediated drug efflux and supports the hypothesis that it may inhibit resistance mediated by MDR1 and MRP proteins. Even if its reversal activity is insufficient for clinical application, its capacity to accumulate [3 H]-vinblastine in MDCK/MDR1 and MCF7/Dox cells suggests that eudesmin may positively affect the bioavailability and, thereby, the therapeutic potency of anticancer drugs in Pgp-overexpressing cells. Diphyllin exhibits IC50 values ranging from 10 - 6 to 10 - 4 M. It is markedly less toxic than podophyllotoxin (IC50 : 13 - 61 nM), but exhibits tumoricidal effects close to those of etoposide. Unfortunatly, it is 65-fold more toxic than etoposide on human primary fibroblasts. Consequently, it has no value as an anticancer drug. Its value as raw material for the hemisynthesis of anticancer drugs is discussed.

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Prof. Chantal Barthomeuf

INSERM-484

Laboratoire de Pharmacognosie et Biotechnologies

Faculté de Pharmacie, Université d’Auvergne

63001 Clermont-Ferrand

France

Phone: +33-4-7317-8026

Fax: +33-4-7317-8026

Email: Chantal.Barthomeuf@u-clermont1.fr

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