title: Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway.
abstract: Pancreatic cancer is one of the most difficult malignancies to treat owing to the rapid acquisition of resistance to chemotherapy. Gemcitabine, a first-line treatment for pancreatic cancer, prolongs patient survival by several months, and combination treatment with gemcitabine and other anti-cancer drugs in the clinic do not show any significant effects on overall survival. Thus, identification of a drug that resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine and a better understanding of the molecular mechanisms of gemcitabine resistance are critical to develop new therapeutic options for pancreatic cancer. Here, we report that zidovudine resensitizes gemcitabine-resistant pancreatic cancer to gemcitabine as shown by screening a compound library, including clinical medicine, using gemcitabine-resistant cells. In analyzing the molecular mechanisms of zidovudine effects, we found that the epithelial-to-mesenchymal transition (EMT)-like phenotype and downregulation of human equilibrative nucleoside transporter 1 (hENT1) are essential for the acquisition of gemcitabine resistance, and zidovudine restored these changes. The chemical biology investigations also revealed that activation of the Akt-GSK3β-Snail1 pathway in resistant cells is a key signaling event for gemcitabine resistance, and zidovudine resensitized resistant cells to gemcitabine by inhibiting this activated pathway. Moreover, our in vivo study demonstrated that co-administration of zidovudine and gemcitabine strongly suppressed the formation of tumors by gemcitabine-resistant pancreatic cancer and prevented gemcitabine-sensitive pancreatic tumors from acquiring gemcitabine-resistant properties, inducing an EMT-like phenotype and downregulating hENT1 expression. These results suggested that co-treatment with zidovudine and gemcitabine may become a novel therapeutic strategy for pancreatic cancer by inhibiting chemoresistance-specific signaling.
authors.affiliation: Science Research Center, Kochi University, Kochi 783-8505, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Namba
authors.affiliation: Science Research Center, Kochi University, Kochi 783-8505, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Kodama
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Moritomo
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hoshino
authors.affiliation: Department of Analytical Chemistry, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000998:Antiviral Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D033721:Equilibrative Nucleoside Transporter 1 / Q000096:biosynthesis / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D015215:Zidovudine / Q000627:therapeutic use*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D033721:Equilibrative Nucleoside Transporter 1; D034741:RNA, Small Interfering; C438649:SLC29A1 protein, human; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D003841:Deoxycytidine; D015215:Zidovudine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000093542:Gemcitabine