title: Reversal of P-glycoprotein-mediated drug efflux by eudesmin from Haplophyllum perforatum and cytotoxicity pattern versus diphyllin, podophyllotoxin and etoposide.
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 IC (50) values > 100 microM 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 IC (50) values ranging from 10 (- 6) to 10 (- 4) M. It is markedly less toxic than podophyllotoxin (IC (50) : 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.
authors: INSERM-484, Clermont-Ferrand, France.
authors: Suzanne
authors: S
authors: Lim
authors: Jérôme
authors: J
authors: Grassi
authors: Valentina
authors: V
authors: Akhmedjanova
authors: Eric
authors: E
authors: Debiton
authors: Guy
authors: G
authors: Balansard
authors: Richard
authors: R
authors: Beliveau
authors: Chantal
authors: C
authors: Barthomeuf
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D052117:Benzodioxoles; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D004148:Dioxolanes / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D017705:Lignans / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D018515:Plant Leaves; D018517:Plant Roots; D011034:Podophyllotoxin / Q000494:pharmacology; D027821:Rutaceae
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D052117:Benzodioxoles; D004148:Dioxolanes; D005663:Furans; D017705:Lignans; D010936:Plant Extracts; C105875:eudesmin; D005047:Etoposide; D011034:Podophyllotoxin; C010130:diphyllin