論文 - 詳細
| RRC ID | 37526 |
|---|---|
| 著者 | Namba T, Kodama R, Moritomo S, Hoshino T, Mizushima T. |
| タイトル | Zidovudine, an anti-viral drug, resensitizes gemcitabine-resistant pancreatic cancer cells to gemcitabine by inhibition of the Akt-GSK3β-Snail pathway. |
| ジャーナル | Cell Death Dis |
| 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. |
| 巻・号 | 6(6) |
| ページ | e1795 |
| 公開日 | 2015-6-25 |
| DOI | 10.1038/cddis.2015.172 |
| PII | cddis2015172 |
| PMID | 26111057 |
| PMC | PMC4669843 |
| MeSH | Animals Antimetabolites, Antineoplastic / therapeutic use Antiviral Agents / therapeutic use* Apoptosis / drug effects Cell Line, Tumor Cell Movement / genetics Cell Survival / drug effects Deoxycytidine / analogs & derivatives* Deoxycytidine / therapeutic use Drug Resistance, Neoplasm / drug effects* Equilibrative Nucleoside Transporter 1 / biosynthesis Equilibrative Nucleoside Transporter 1 / genetics Gemcitabine Glycogen Synthase Kinase 3 / antagonists & inhibitors Glycogen Synthase Kinase 3 beta Humans Mice Mice, Inbred BALB C Mice, Nude Neoplasm Invasiveness / genetics Pancreatic Neoplasms / drug therapy* Proto-Oncogene Proteins c-akt / antagonists & inhibitors RNA Interference RNA, Small Interfering Snail Family Transcription Factors Transcription Factors / antagonists & inhibitors Transcription Factors / genetics Up-Regulation / drug effects Xenograft Model Antitumor Assays Zidovudine / therapeutic use* |
| IF | 6.304 |
| 引用数 | 31 |
| WOS 分野 | CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | PK-1(RCB1972) KLM-1(RCB2138) |