Farnesiferol A from Ferula persica and Galbanic Acid from Ferula szowitsiana Inhibit P-Glycoprotein-Mediated Rhodamine Efflux in Breast Cancer Cell Lines

Abstract

In multidrug resistance (MDR), cancer cells exposed to anticancer agents develop resistance to a wide variety of chemicals and chemotherapeutic agents. Sesquiterpene coumarins are reported to inhibit P-glycoprotein and/or increase cytotoxicity of anticancer drugs in P‐gp-overexpressing cell lines.

In the current study, we investigated the effects of galbanic acid (from the roots of Ferula szowitsiana) and farnesiferol A (from the roots of Ferula persica) on functionality of the drug transporter P-glycoprotein (P‐gp) using a rhodamine 123 efflux assay in a doxorubicin resistant breast cancer cell line (MCF7/Adr).

Compared to verapamil, the well-known inhibitor of P‐gp, galbanic acid (5, 10, and 25 µg/mL), significantly inhibited the P‐gp activity. In inhibition of the P‐gp transporter, farnesiferol A (0.5 µg/mL) was more potent than verapamil at 15 min exposure.

Our results indicate that the plant derived sesquiterpene coumarins, farnesiferol A and galbanic acid, may be promising candidates to be considered for further studies on the reversal of multidrug resistance phenotype in chemotherapy of cancer patients.

Key words

P‐glycoprotein - MDR - farnesiferol A - galbanic acid - Ferula persica - Apiaceae

References

• 1 Liscovitch M, Lavie Y. Cancer multidrug resistance: a review of recent drug discovery research.  Drugs. 2002;  5 349-355
• 2 Ambudkar S V, Dey S, Hrycyna C A, Ramachandra M, Pastan I, Gottesman M M. Biochemical, cellular, and pharmacological aspects of the multidrug transporter.  Annu Rev Pharmacol Toxicol. 1999;  39 361-398
• 3 Sharom F J. The P-glycoprotein efflux pump: how does it transport drugs?.  J Membr Biol. 1997;  160 161-175
• 4 Thiebaut F, Tsuruo T, Hamada H, Gottesman M M, Pastan I, Willingham M C. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues.  Proc Natl Acad Sci USA. 1987;  84 7735-7738
• 5 Abd El-Razek M H, Ohta S, Hirata T. Terpenoid coumarins of the genus Ferula.  Heterocycles. 2003;  60 689-716
• 6 Pimenov M G, Leonov M V. The asian umbelliferae biodiversity database (ASIUM) with particular reference to south-west asian taxa.  Turk J Bot. 2004;  28 139-145
• 7 Barthomeuf C, Demeule M, Grassi J, Saidkhodjaev A, Beliveau R. Conferone from Ferula schtschurowskiana enhances vinblastine cytotoxicity in MDCK-MDR1 cells by competitively inhibiting P-glycoprotein transport.  Planta Med. 2006;  72 634-639
• 8 Madureira A M, Molnar A, Abreu P M, Molnar J, Ferreira M J U. A new sesquiterpene-coumarin ether and a new abietane diterpene and their effects as inhibitors of P-glycoprotein.  Planta Med. 2004;  70 828-833
• 9 Behnam Rassouli F, Matin M M, Iranshahi M, Bahrami A R, Neshati V, Mollazadeh S, Neshati Z. Mogoltacin enhances vincristine cytotoxicity in human transitional cell carcinoma (TCC) cell line.  Phytomedicine. 2009;  16 181-187
• 10 Iranshahi M, Kalategi F, Rezaee R, Shahverdi A R, Ito C, Furukawa H, Tokuda H, Itoigawa M. Cancer chemopreventive activity of terpenoid coumarins from Ferula species.  Planta Med. 2008;  74 147-150
• 11 Iranshahi M, Arfa P, Ramezani M, Jaafari M R, Sadeghian H, Bassarello C, Piacente S, Pizza C. Sesquiterpene coumarins from Ferula szowitsiana and in vitro antileishmanial activity of 7-prenyloxycoumarins against promastigotes.  Phytochemistry. 2007;  68 554-561
• 12 Iranshahi M, Amin G, Shafiee A. A new coumarin from Ferula persica.  Pharm Biol. 2004;  42 440-442
• 13 Gedeon C, Behravan J, Koren G, Piquette-Miller M. Transport of glyburide by placental ABC transporters: implications in fetal drug exposure.  Placenta. 2006;  27 1096-1102
• 14 Ikegawa T, Ohtani H, Koyabu N, Juichi M, Iwase Y, Ito C, Furukawa H, Naito M, Tsuruo T, Sawada Y. Inhibition of P-glycoprotein by flavonoid derivatives in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells.  Cancer Lett. 2002;  177 89-93
• 15 Bradford M M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.  Anal Biochem. 1976;  72 248-254
• 16 Kusuhara H, Suzuki H, Sugiyama Y. The role of P-glycoprotein and canalicular multispecific organic anion transporter in the hepatobiliary excretion of drugs.  J Pharm Sci. 1998;  87 1025-1040
• 17 Ma Y, Wink M. Lobeline, a piperidine alkaloid from Lobelia can reverse P-gp dependent multidrug resistance in tumor cells.  Phytomedicine. 2008;  15 754-758
• 18 Oughlissi-Dehak K, Lawton P, Michalet S, Bayet C, Darbour N, Hadj-Mahammed M, Badjah-Hadj-Ahmed Y A, Dijoux-Franca M G, Guilet D. Sesquiterpenes from aerial parts of Ferula vesceritensis.  Phytochemistry. 2008;  69 1933-1938
• 19 Raub T J. P-glycoprotein recognition of substrates and circumvention through rational drug design.  Mol Pharm. 2006;  3 3-25