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Planta Med 2006; 72(7): 634-639
DOI: 10.1055/s-2006-931574
Original Paper
Biochemistry and Molecular Biology
© Georg Thieme Verlag KG Stuttgart · New York

Conferone from Ferula schtschurowskiana Enhances Vinblastine Cytotoxicity in MDCK-MDR1 Cells by Competitively Inhibiting P-Glycoprotein Transport

Chantal Barthomeuf1 , Michel Demeule2 , Jérôme Grassi2 , Ashraf Saidkhodjaev3 , Richard Beliveau2
  • 1UMR: INSERM U-484, Université d’Auvergne, Centre hospitalier J. Perrin, Laboratoire de Pharmacognosie et de Biotechnologie, Faculté de Pharmacie, Clermont-Ferrand, France
  • 2Laboratoire de Médecine Moléculaire, Service d'Hémato-Oncologie, Hôpital Ste-Justine-UQAM, Montréal, Québec, Canada
  • 3Laboratory of the Chemistry of Coumarins and Terpenoids, S .Yu. Yunusov Institute of the Chemistry of Plant Substances, Tashkent, Uzbekistan
Further Information

Publication History

Received: December 6, 2005

Accepted: January 31, 2006

Publication Date:
31 May 2006 (online)

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Abstract

Overexpression of the protein transporter P-glycoprotein (Pgp, MDR1) at the cell surface is a major cause of multidrug resistance (MDR) and poor response to treatment in cancer chemotherapy and therapy for leishmaniasis. The present study shows that conferone, a sesquiterpene coumarin ether isolated for the first time from Ferula schtschurowskiana, endemic in Uzbekistan, enhances the cell toxicity of vinblastine (VBL) in MDR1-transfected Madin-Darby canine kidney (MDCK-MDR1) cells. Conferone presents the advantage to mediate this effect at safe concentrations. At 10 μM, it efficiently competes with the photoactivatable cyclosporin A analogue (SDZ 212 - 122) for the binding to Pgp and accumulates [3 H]-VBL to a higher extent than cyclosporin A or cnidiadin. [3 H]-VBL accumulation is dose-dependent and correlates with the inhibition of Pgp photolabeling affinity, supporting the hypothesis that conferone sensitizes MDCK-MDR1 cells to VBL by competitively inhibiting drug efflux. In MDCK-MDR1 cells, [3 H]-VBL accumulation appears to be almost completely dependent on inhibition of Pgp transport. However, the strict specificity of conferone to this efflux pump has to be demonstrated in cell lines expressing other protein transporters. Collectively, our findings identify conferone as a powerful modulator of Pgp transport and a promising molecule for the treatment of MDR malignancies and leishmaniasis. Complementary in vitro and in vivo studies are, however, needed to assess the value of conferone as a reversal drug in human therapy. Considering its high affinity for Pgp, conferone may have an additional usefulness as a tool for the design or the (hemi)synthesis of agents probing Pgp. To our knowledge, this is the first report identifying sesquiterpene coumarins from Ferula as possible drug candidates for the reversion of MDR encoded by the MDR1 gene or the synthesis of agents probing Pgp.

Key words

Cancer - conferone - sesquiterpene coumarin - multidrug resistance - P-glycoprotein (Pgp, MDR1) - reversal activity - photolabeling - Ferula schtschurowskiana - Apiaceae

References

  • 1 Leonard G D, Fojo T, Bates S E. The role of ABC transporters in clinical practice.  Oncologist. 2003;  8 411-24
    CrossrefPubMedSearch in Google Scholar
  • 2 Demeule M, Regina A, Jodoin J, Laplante A, Dagenais C, Berthelet F. et al . Drug transport to the brain: key roles for the efflux pump P-glycoprotein in the blood-brain barrier.  Vascul Pharmacol. 2002;  38 339-48
    CrossrefPubMedSearch in Google Scholar
  • 3 Laing N M, Tew K D. Drug resistance to chemotherapy, mechanisms. In: Bertino JR, editor Encyclopedia of cancer. Vol. 1 San Diego; Academic Press 1997: p 560-70
    Search in Google Scholar
  • 4 Ambudkar S V, Kimchi-Sarfaty C, Sauna Z E, Gottesman M M. P-glycoprotein: from genomics to mechanism.  Oncogene. 2003;  22 7468-85
    CrossrefPubMedSearch in Google Scholar
  • 5 Trambas C M, Muller H K, Woods G M. P-glycoprotein mediated multidrug resistance and its implications for pathology.  Pathology. 1997;  29 122-30
    CrossrefPubMedSearch in Google Scholar
  • 6 Benard J, Bourhis J, de Vathaire F, Ferrandis E, Terrier-Lacombe M J, Lemerle J. et al . Prognostic value of MDR1 gene expression in neuroblastoma: results of a multivariate analysis.  Prog Clin Biol Res. 1994;  385 111-6
    PubMedSearch in Google Scholar
  • 7 Madureira A M, Molnar A, Abreu P M, Molnar J, Ferreira M J. A new sesquiterpene-coumarin ether and a new abietane diterpene and their effects as inhibitors of P-glycoprotein.  Planta Med. 2004;  70 828-33
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Munoz-Martinez F, Lu P, Cortes-Selva F, Perez-Victoria J M, Jimenez I A, Ravelo A G. et al . Celastraceae sesquiterpenes as a new class of modulators that bind specifically to human P-glycoprotein and reverse cellular multidrug resistance.  Cancer Res. 2004;  64 7130-8
    CrossrefPubMedSearch in Google Scholar
  • 9 Cortes-Selva F, Jimenez I A, Munoz-Martinez F, Campillo M, Bazzocchil L, Pardo L. et al . Dihydro-beta-agarofuran sesquiterpenes: a new class of reversal agents of the multidrug resistance phenotype mediated by P-glycoprotein in the protozoan parasite Leishmania .  . 2005;  11 3125-39
    PubMedSearch in Google Scholar
  • 10 Barthomeuf C, Grassi J, Demeule M, Fournier C, Boivin D, Beliveau R. Inhibition of P-glycoprotein transport function and reversion of MDR1 multidrug resistance by cnidiadin.  Cancer Chemother Pharmacol. 2005;  56 173-81
    CrossrefPubMedSearch in Google Scholar
  • 11 Miski M, Ulubelen A. Sesquiterpene-coumarin ethers of Ferula tingitana .  J Nat Prod. 1985;  48 326-7
    CrossrefPubMedSearch in Google Scholar
  • 12 Abd El-Razek M H, Ohta S, Ahmed A A, Hirata T. Sesquiterpene coumarins from the roots of Ferula assa-foetida .  Phytochemistry. 2001;  58 1289-95
    CrossrefPubMedSearch in Google Scholar
  • 13 Isaka K, Nagatsu A, Ondognii P, Zevgeegiin O, Gombosurengyin P, Davgiin K. et al . Sesquiterpenoid derivatives from Ferula ferulaeoides .  Chem Pharm Bull 2001; 49 : 1072 - 6; Erratum: Chem Pharm Bull. 2002;  50 885
    PubMedSearch in Google Scholar
  • 14 Motai T, Kitanaka S. Sesquiterpene coumarins from Ferula fukanensis and nitric oxide production inhibitory effects.  Chem Pharm Bull. 2004;  52 1215-8
    CrossrefPubMedSearch in Google Scholar
  • 15 Vandyshev V V, Sklyar Y E, Perel’son M E, Moroz M D, Pimenov M G. Conferone; a new terpenoid coumarin from fruit of Ferula conocaula .  Chem Nat Compd (A translation of Him Prir Soed). 1972;  8 653
    PubMedSearch in Google Scholar
  • 16 Barthomeuf C, Boivin D, Beliveau R. Inhibition of HUVEC tubulogenesis by hederacolchiside-A1 is associated with plasma membrane cholesterol sequestration and activation of the Ha-Ras/MEK/ERK cascade.  Cancer Chemother Pharmacol. 2004;  54 432-40
    CrossrefPubMedSearch in Google Scholar
  • 17 Demeule M, Laplante A, Sepehr-Arae A, Beaulieu E, Averill-Bates D, Wenger R M. et al . Inhibition of P-glycoprotein by cyclosporin A analogues and metabolites.  Biochem Cell Biol. 1999;  77 47-58
    CrossrefPubMedSearch in Google Scholar
  • 18 Bodo A, Bakos E, Szeri F, Varadi A, Sarkadi B. The role of multidrug transporters in drug availability, metabolism and toxicity.  Toxicol Lett. 2003;  140 - 1 133-43
    CrossrefPubMedSearch in Google Scholar
  • 19 Leslie E M, Mao Q, Oleschuk C J, Deeley R G, Cole S P. Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and ATPase activities by interaction with dietary flavonoids.  Mol Pharmacol. 2001;  59 1171-80
    PubMedSearch in Google Scholar
  • 20 Hsiu S L, Hou Y C, Wang Y H, Tsao C W, Su S F, Chao P D. Quercetin significantly decreased cyclosporin oral bioavailability in pigs and rats.  Life Sci. 2002;  72 227-35
    CrossrefPubMedSearch in Google Scholar
  • 21 Limtrakul P, Khantamat O, Pintha K. Inhibition of P-glycoprotein function and expression by kaempferol and quercetin.  J Chemother. 2005;  17 86-95
    PubMedSearch in Google Scholar
  • 22 Duraj J, Zazrivcova K, Bodo J, Sulikova M, Sedlak J. Flavonoid quercetin, but not apigenin or luteolin, induced apoptosis in human myeloid leukemia cells and their resistant variants.  Neoplasma. 2005;  52 273-9
    PubMedSearch in Google Scholar
  • 23 Rosenbaum C, Rohrs S, Muller O, Waldmann H. Modulation of MRP-1-mediated multidrug resistance by indomethacin analogues.  J Med Chem. 2005;  48 1179-87
    CrossrefPubMedSearch in Google Scholar
  • 24 Munoz-Martinez F, Mendoza C R, Bazzocchi I L, Castanys S, Jimenez I A, Ravelo A G. et al . Reversion of human Pgp-dependent multidrug resistance by new sesquiterpenes from Zinowiewia costaricensis. J.  Med Chem. 2005;  48 4266-75
    CrossrefPubMedSearch in Google Scholar

Prof. Chantal Barthomeuf

UMR: INSERM U-484

Université d’Auvergne

Centre hospitalier J. Perrin

Laboratoire de Pharmacognosie et de Biotechnologies

Faculté de Pharmacie

Place H. Dunant

63001 Clermont-Ferrand

France

Phone: +33-4-73-17-80-26

Fax: +33-4-73-15-08-01

Email: chantal.barthomeuf@u-clermont1.fr