title: EM-E-11-4 increases paclitaxel uptake by inhibiting P-glycoprotein-mediated transport in Caco-2 cells.
abstract: P-glycoprotein (P-gp) overexpression is the main mechanism involved in chemotherapy drug resistance such as paclitaxel resistance and therapy failure. The most widely studied P-gp inhibitors still have limited ability to reverse resistance in the clinic. In this study, EM-E-11-4, a lathyrane-type diterpenoid isolated from Euphorbia micractina, was found to significantly increase paclitaxel uptake in Caco-2 cells, which functionally overexpressed P-gp. In vitro transport experiments, carried out in the Caco-2 monolayer model, indicated that EM-E-11-4 significantly reduced the efflux ratio of paclitaxel transport by inhibiting P-gp function without affecting P-gp expression. We also found that EM-E-11-4 enhanced the intracellular accumulation of paclitaxel in a dose-dependent manner by LC-MS/MS and EM-E-11-4 showed low cytotoxicity. Hence, EM-E-11-4 is an effective potential agent to reverse P-gp-mediated paclitaxel resistance by inhibiting P-gp transport function and increasing the intracellular concentration of paclitaxel.
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: Qian
authors.initials: Q
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Sun
authors.forename: Xiao-Guang
authors.initials: XG
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: You
authors.forename: Xiu-Qi
authors.initials: XQ
authors.lastname: Bao
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Jian-Gong
authors.initials: JG
authors.lastname: Shi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000494:pharmacology; D018938:Caco-2 Cells; D004224:Diterpenes / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D017239:Paclitaxel / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D004224:Diterpenes; C000602156:EM-E-11-4; D017239:Paclitaxel
keywords: EM-E-11-4; Euphorbia micractina; P-glycoprotein; drug resistance; paclitaxel; reversing agents