title: Reversal of P-glycoprotein-mediated multidrug resistance by the novel tetrandrine derivative W6.
abstract: Overexpression of ATP-dependent efflux pump P-glycoprotein (P-gp) is the main cause of multidrug resistance (MDR) and chemotherapy failure in cancer treatment. Inhibition of P-gp-mediated drug efflux is an effective way to overcome cancer drug resistance. The present study investigated the reversal effect of the novel tetrandrine derivative W6 on P-gp-mediated MDR. KBv200, MCF-7/adr and their parental sensitive cell lines KB, MCF-7 were used for reversal study. The intracellular accumulation with P-gp substrates of doxorubicin was determined by flow cytometry. The expression of P-gp and ERK1/2 was investigated by western blot and real-time-PCR (RT-PCR) analysis. ATPase activity of P-gp was performed by P-gp-Glo(TM) assay systems. In comparison with P-gp-negative parental cells, W6 produced a favorable reversal effect in the MDR cells, as determined using the MTT assay. W6 significantly and dose-dependently increased intracellular accumulation of P-gp substrate doxorubicin (DOX) in P-gp overexpressing KBv200 cells, and also inhibited the ATPase activity of P-gp. W6 inhibited P-gp expression in KBv200 cells in a time-dependent manner, but it had no effect on MDR1 expression. In addition, W6 significantly decreased the ERK1/2 activation in KBv200 cells. Our results showed that W6 effectively reversed P-gp-mediated MDR by inhibiting the transport function and expression of P-gp, demonstrating the potential clinical utility of W6.
authors.affiliation: a State Key Laboratory of Bioactive Substance and Function of Natural Medicines , Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 , China.
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Feng-Peng
authors.initials: FP
authors.lastname: Wang
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Bao
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D044182:Benzylisoquinolines / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007624:KB Cells; D015394:Molecular Structure
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D044182:Benzylisoquinolines; C000602264:tetrandrine derivative W6; C009438:tetrandrine; D004317:Doxorubicin
keywords: P-glycoprotein; Stephania tetrandra; W6; multidrug resistance; reversing agents; tetrandrine