title: Downregulation of P-gp, Ras and p-ERK1/2 contributes to the arsenic trioxide-induced reduction in drug resistance towards doxorubicin in gastric cancer cell lines.
abstract: Multidrug resistance (MDR) to doxorubicin (DOX) limits its effectiveness against tumor cells. Arsenic trioxide (As2O3) has been reported to reduce MDR in various types of cancer, but the mechanisms involving Ras and p-glycoprotein (P-gp) remain to be fully elucidated. The objectives of the present study were to evaluate As2O3 in reversing MDR to DOX, and to identify the association in antitumor activities between the effectiveness of DOX and Ras/phosphorylated (p‑) extracellular signal‑regulated kinase (ERK)1/2 signaling in SGC7901/ADM and SGC7901/S human gastric cancer cell lines. Cytotoxicity and sensitivity towards As2O3 were assessed using non‑toxic and mildly‑toxic concentrations (0.1 and 0.5 µM, respectively). The reversing effect of As2O3 on MDR was investigated prior to and following treatment with a cytokine activation of the recombinant human granulocyte colony stimulating factor ERK pathway. The SGC7901/ADM and SGC7901/S cells had the same sensitivity to As2O3. The SGC7901/ADM cells were resistant to DOX and As2O3 treatment reduced the level of resistance to DOX (P<0.01). The expression of P‑glycoprotein (P-gp) in the SGC7901/ADM cells was higher than in the SGC7901/S cells (P<0.001). As2O3 treatment decreased the levels of P‑gp in a time‑ and dose‑dependent manner (P<0.01). The expression of Ras was higher in the SGC7901/ADM cells than in the SGC7901/S cells, while the expression of p‑ERK1/2 remained the same. As2O3 decreased the levels of Ras and p‑ERK1/2 (P<0.01). Following pretreatment with rhG‑CSF, the levels of Ras and p‑ERK1/2 were further decreased (P<0.01). Drug‑resistant gastric cancer cells had higher expression levels of P‑gp and Ras, but not of p‑ERK1/2. Non‑ and mildly‑toxic doses of As2O3 reduced MDR to DOX through Ras/p-ERK1/2 signaling.
authors.affiliation: Department of Oncology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266000, P.R. China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Department of Oncology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266000, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Oncology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266000, P.R. China.
authors.forename: Bao-Ling
authors.initials: BL
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266000, P.R. China.
authors.forename: Xin-Jia
authors.initials: XJ
authors.lastname: He
authors.affiliation: Department of Oncology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266000, P.R. China.
authors.forename: Bi-Yuan
authors.initials: BY
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D004317:Doxorubicin; D018631:ras Proteins; D000077237:Arsenic Trioxide