title: Potent modulation of P-glycoprotein activity by naturally occurring phenylbutenoids from Zingiber cassumunar.
abstract: Five phenylbutenoid derivatives from the rhizomes of Zingiber cassumunar Roxb. (Zingiberaceae) were evaluated for their P-glycoprotein (P-gp) inhibitory effects in a P-gp over-expressing multidrug resistant (MDR) human breast cancer cell line, MCF-7/ADR. As a result, a phenylbutenoid dimer, (+/-)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene (1), exhibited highly potent P-gp inhibitory activity, decreasing the IC(50) value of daunomycin (DNM) to 4.31 +/- 0.40 microm in the cells (DNM IC(50) = 37.1 +/- 0.59 microm). The positive control, verapamil decreased the IC(50) value of DNM to 6.94 +/- 0.40 microm. Three phenylbutenoid monomers, 2-4 from this plant, also resulted in a significant decrease in the IC(50) values of DNM compared with the control. In particular, compound 1 markedly enhanced [(3)H]-DNM accumulation and significantly reduced [(3)H]-DNM efflux compared with the control, and this effect was more potent than that of verapamil, a well-known P-gp inhibitor. These results suggest that compound 1 of Z. cassumunar can be developed as a potent chemo-sensitizing agent that reverses P-gp-mediated MDR in human cancer chemotherapy.
authors.affiliation: College of Pharmacy, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Chung
authors.forename: Ah-Reum
authors.initials: AR
authors.lastname: Han
authors.forename: Min Kyung
authors.initials: MK
authors.lastname: Sung
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: Jung
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Nam
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Seo
authors.forename: Hwa Jeong
authors.initials: HJ
authors.lastname: Lee
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D053138:Cyclohexenes / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D027343:Rhizome / Q000737:chemistry; D014700:Verapamil / Q000494:pharmacology; D030521:Zingiberaceae / Q000737:chemistry*; D013343:Styrenes
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D053138:Cyclohexenes; D003630:Daunorubicin; D014700:Verapamil; C522789:trans-3-(3,4-dimethoxyphenyl)-4-((E)-3,4-dimethoxystyryl)cyclohex-1-ene; D013343:Styrenes