Modulation of Multidrug Resistance Protein 2 Efflux in the Cisplatin Resistance Human Ovarian Carcinoma Cells A2780/RCIS by Sesquiterpene Coumarins.
Recent in vitro studies showed that sesquiterpene coumarins (SCs) can be used as chemosensitizers. In this study, 14 SCs were isolated and purified from roots of four Ferula species and their structures were elucidated by spectroscopic methods. The purified SCs were evaluated for multidrug resistance (MDR) reversal properties in A2780/RCIS cells (cisplatin-resistant derivatives of the human ovarian carcinoma cell line A2780P). Among the tested compounds, mogoltacin, mogoltadone, farnesiferol A, farnesiferol B, farnesiferol C, lehmferin, conferdione, and samarcandin showed significant MDR reversing effects. The combination of nontoxic concentrations of SCs (20 μM) with cisplatin enhanced cisplatin cytotoxicity on A2780/RCIS cells significantly. Flow cytometric efflux assay confirmed that the intracellular accumulation of 5-carboxyfluorescein diacetate (5-CFDA) was significantly increased in A2780/RCIS cells when treated with SCs. Our findings revealed that conferdione and samarcandin possessed the highest inhibitory effects on multidrug resistance-associated protein 2 pump efflux, and therefore, these compounds could be considered as lead scaffolds for further structure modifications.
Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Jamal
J
Kasaian
Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Fatemeh
F
Mosaffa
Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Javad
J
Behravan
Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, Salerno, 84084, Italy.
Milena
M
Masullo
Dipartimento di Farmacia, Università degli Studi di Salerno, Via Giovanni Paolo II, Salerno, 84084, Italy.
Sonia
S
Piacente
Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Mehrdad
M
Iranshahi
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003374:Coumarins / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D005309:Ferula / Q000737:chemistry; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology*; D018517:Plant Roots / Q000737:chemistry; D012717:Sesquiterpenes / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D002945:Cisplatin; D003374:Coumarins; D005452:Fluoresceins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012717:Sesquiterpenes; C539928:mogoltacin; C553326:farnesiferol C; C084577:5-carboxyfluorescein diacetate; C579605:farnesiferol A; C551830:farnesiferol B
Apiaceae; Ferula flabelliloba; Ferula galbaniflua; Ferula gummosa; Ferula szowitsiana; multidrug resistance protein 2; ovarian carcinoma