title: N1-guanyl-1,7-diaminoheptane sensitizes bladder cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation.
abstract: Drug resistance greatly reduces the efficacy of doxorubicin-based chemotherapy in bladder cancer treatment; however, the underlying mechanisms are poorly understood. We aimed to investigate whether N1-guanyl-1,7-diaminoheptane (GC7), which inhibits eukaryotic translation initiation factor 5A2 (eIF5A2) activation, exerts synergistic cytotoxicity with doxorubicin in bladder cancer, and whether eIF5A2 is involved in chemoresistance to doxorubicin-based bladder cancer treatment. BIU-87, J82, and UM-UC-3 bladder cancer cells were transfected with eIF5A2 siRNA or negative control siRNA before incubation with doxorubicin alone or doxorubicin plus GC7 for 48 h. Doxorubicin cytotoxicity was enhanced by GC7 in BIU-87, J82, and UM-UC-3 cells. It significantly inhibited activity of eIF5A2, suppressed doxorubicin-induced epithelial-mesenchymal transition in BIU-87 cells, and promoted mesenchymal-epithelial transition in J82 and UM-UC-3 cells. Knockdown of eIF5A2 sensitized bladder cancer cells to doxorubicin, prevented doxorubicin-induced EMT in BIU-87 cells, and encouraged mesenchymal-epithelial transition in J82 and UM-UC-3 cells. Combination therapy with GC7 may enhance the therapeutic efficacy of doxorubicin in bladder cancer by inhibiting eIF5A2 activation and preventing epithelial-mesenchymal transition.
authors.affiliation: Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Yang
authors.forename: Haogang
authors.initials: H
authors.lastname: Yu
authors.forename: Mo
authors.initials: M
authors.lastname: Shen
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Lihong
authors.initials: L
authors.lastname: Xia
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000097574:Eukaryotic Translation Initiation Factor 5A
chemical_list: D004317:Doxorubicin; D006147:Guanine; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D000097574:Eukaryotic Translation Initiation Factor 5A; C100667:N(1)-guanyl-1,7-diaminoheptane
keywords: Doxorubicin; drug resistance; epithelial-mesenchymal transition; eukaryotic translation initiation factor 5A; urinary bladder neoplasms