title: Bufalin reverses intrinsic and acquired drug resistance to cisplatin through the AKT signaling pathway in gastric cancer cells.
abstract: Cisplatin is the most common chemotherapeutic agent for gastric cancer (GC), however it activates AKT, which contributes to intrinsic and acquired resistance. Bufalin, a traditional Chinese medicine, shows significant anticancer activity by inhibiting the AKT pathway. It was therefore hypothesized that bufalin could counteract cisplatin resistance in GC cells. SGC7901, MKN‑45 and BGC823 human GC cells were cultured under normoxic and hypoxic conditions. Effects of cisplatin and bufalin on GC cells were measured by a cell counting kit, apoptosis was analyzed by flow cytometry, and immunoblotting was used to detect proteins associated with the AKT signaling pathway. It was demonstrated that bufalin synergized with cisplatin to inhibit proliferation and promote apoptosis of GC cells by diminishing the activation of cisplatin-induced AKT under normoxic and hypoxic conditions. Bufalin also inhibits cisplatin-activated molecules downstream of AKT that affect proliferation and apoptosis, including glycogen synthase kinase, mammalian target of rapamycin, ribosomal protein S6 Kinase and eukaryotic translation initiation factor-4E-binding protein-1. To investigate acquired cisplatin resistance, a cisplatin‑resistant cell line SGC7901‑CR was used. It was demonstrated that bufalin reversed acquired cisplatin resistance and significantly induced apoptosis through the AKT pathway. These results imply that bufalin could extend the therapeutic effect of cisplatin on GC cells when administered in combination.
authors.affiliation: Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Dali
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Gastroenterology, The Fourth Hospital of Harbin, Harbin, Heilongjiang 150026, P.R. China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Gastroenterology, The Fourth Hospital of Harbin, Harbin, Heilongjiang 150026, P.R. China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Gastroenterology, The Fourth Hospital of Harbin, Harbin, Heilongjiang 150026, P.R. China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Department of Gastroenterology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Tiefu
authors.initials: T
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002018:Bufanolides; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin; C022777:bufalin