title: Inhibition of P-glycoprotein and glutathione S-transferase-pi mediated resistance by fluoxetine in MCF-7/ADM cells.
abstract: Chemotherapy is important in the systematic treatment of breast cancer. While multidrug resistance (MDR) is the main obstacle in chemotherapy, a reversal reagent with high reversal effect but low toxicity is the hotspot issue at present to overcome MDR. Antidepressant fluoxetine (FLX) is a potential new highly effective chemosensitizer, however, the possible mechanism is unclear. In this study, the effect of FLX on multidrug resistance mediated by P-glycoprotein (P-gp) and glutathione S-transferase-pi (GST-π) were researched in resistant/sensitive breast cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to determine the cells viability after being incubated with FLX/Adriamycin (ADM)/Paclitaxel (PTX) alone or FLX-ADM, FLX-PTX combination. Western blot was performed to assay the expression of P-gp and GST-π proteins. Reverse transcriptase polymerase chain reaction (RT-PCR) and quantitative real-time PCR (qRT-PCR) were performed to assay the level of MDR1 mRNA. The results showed that pre-treatment with FLX enhance cytotoxicity significantly both on resistant and sensitive cells, downregulated the expression of P-gp and GST-π proteins in resistance cells, decreased the MDR1 mRNA by FLX-PTX combination only. No P-gp and GST-π were detected in sensitive cells. Our research thus indicated that FLX reverse the breast cancer cell's resistance and enhance the chemosensitivity by regulating P-gp and GST-π levels.
authors.affiliation: Department of Clinical Pharmacology, Fengxian Central Hospital, Shanghai Jiao Tong University, Shanghai 201406, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Jingjing
authors.initials: J
authors.lastname: Duan
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Xiao
authors.forename: Guihua
authors.initials: G
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Xu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005473:Fluoxetine / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors*; D006801:Humans; D061986:MCF-7 Cells; D017239:Paclitaxel / Q000494:pharmacology*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005473:Fluoxetine; D004317:Doxorubicin; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D017239:Paclitaxel
keywords: Fluoxetine; GST-π; Multidrug resistance; P-gp