title: Tamoxifen reduces P-gp-mediated multidrug resistance via inhibiting the PI3K/Akt signaling pathway in ER-negative human gastric cancer cells.
abstract: Multidrug resistance (MDR), mediated by overexpression of drug efflux transporters such as P-glycoprotein (P-gp), is a major problem limiting successful chemotherapy of gastric cancer. Tamoxifen (TAM), a triphenylethylene nonsteroidal antiestrogen agent, shows broad-spectrum antitumor properties. Emerging studies demonstrated that TAM could significantly reduce the MDR in a variety of human cancers. Here we investigated the effects and possible underlying mechanisms of action of TAM on the reversion of MDR in ER-negative human gastric cancer cells. Our results demonstrated that in MDR phenotype SGC7901/CDDP gastric cancer cells TAM dramatically lowered the IC50 of CDDP, 5-FU and ADM, increased the intracellular Rhodamine123 accumulation and induced G0/G1 phase arrest, while G2/M phase decreased accordingly. Furthermore, at the molecular level, TAM substantially decreased the expression of P-gp, p-Akt and the Akt-regulated downstream effectors such as p-GSK-3β, p-BAD, Bcl-XL and cyclinD1 proteins without affecting the expression of t-Akt, t-GSK-3β, t-BAD proteins in SGC7901/CDDP cells. Thus, our findings demonstrate that TAM reverses P-gp-mediated gastric cancer cell MDR via inhibiting the PI3K/Akt signaling pathway.
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China. Electronic address: maozl522026820@163.com.
authors.forename: Zonglei
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China. Electronic address: 13913506369@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: The Occupational Disease Hospital of Zibo, Zibo 255200, China. Electronic address: captin_hsb@163.com.
authors.forename: Junwei
authors.initials: J
authors.lastname: Luan
authors.affiliation: Cell and Molecular Biology Institute, College of Medicine, Soochow University, Suzhou 215123, China. Electronic address: Shengweihua@163.com.
authors.forename: Weihua
authors.initials: W
authors.lastname: Sheng
authors.affiliation: Department of Respiratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, China. Electronic address: 20084032116033@suda.edu.cn.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou 215006, China. Electronic address: dongxq@hotmail.com.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Dong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011960:Receptors, Estrogen; D013629:Tamoxifen; D051057:Proto-Oncogene Proteins c-akt
keywords: Multidrug resistance; PI3K/Akt; Tamoxifen