title: FG020326 sensitized multidrug resistant cancer cells to docetaxel-mediated apoptosis via enhancement of caspases activation.
abstract: Apoptotic resistance is the main obstacle for treating cancer patients with chemotherapeutic drugs. Multidrug resistance (MDR) is often characterized by the expression of P-glycoprotein (P-gp), a 170-KD ATP-dependent drug efflux protein. Functional P-gp can confer resistance to activate caspase-8 and -3 dependent apoptosis induced by a range of different stimuli, including tumor necrosis and chemotherapeutic drugs such as docetaxel and vincristine. We demonstrated here that comparison of sensitive KB cells, P-gp positive (P-gp(+ve)) KBv200 cells were extremely resistant to apoptosis induced by docetaxel. FG020326, a pharmacological inhibitor of P-gp function, could enhance concentration-dependently the effect of docetaxel on cell apoptosis and sensitize caspase-8, -9 and -3 activation in P-gp overexpressing KBv200 cells, but not in KB cells. Therefore, the enhancement of caspase-8, -9 and -3 activation induced by docetaxel may be one of the key mechanisms of the reversal of P-gp mediated docetaxel resistance by FG020326.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-Sen University of Medical Sciences, Guangzhou 510060, China. wnwnwang@163.com
authors.forename: Xiu-Wen
authors.initials: XW
authors.lastname: Wang
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Wang
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Yong-Ju
authors.initials: YJ
authors.lastname: Liang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Shi
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Chen
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000179:Acrylates / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007624:KB Cells; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000179:Acrylates; D000970:Antineoplastic Agents; D007093:Imidazoles; D043823:Taxoids; C531580:methyl 3-(4-(4,5-bis(4-(isopropyl(methyl)amino)phenyl)-1H-imidazol-2-yl)phenyl)acrylate; D000077143:Docetaxel; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9