論文 - 詳細
| RRC ID | 52642 |
|---|---|
| 著者 | Shimada S, Akiyama Y, Mogushi K, Ishigami-Yuasa M, Kagechika H, Nagasaki H, Fukamachi H, Yuasa Y, Tanaka S. |
| タイトル | Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models. |
| ジャーナル | Br J Cancer |
| Abstract |
BACKGROUND:Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells. METHODS:We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents. RESULTS:We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo. CONCLUSIONS:These findings may lead to the development of novel therapeutic strategies targeting DGC. |
| 巻・号 | 118(7) |
| ページ | 972-984 |
| 公開日 | 2018-4-1 |
| DOI | 10.1038/s41416-018-0008-y |
| PII | 10.1038/s41416-018-0008-y |
| PMID | 29527007 |
| PMC | PMC5931092 |
| MeSH | Animals Antineoplastic Agents / classification Antineoplastic Agents / pharmacology* Antineoplastic Agents / therapeutic use Cdh1 Proteins / genetics Cell Line, Tumor Disease Models, Animal Drug Screening Assays, Antitumor Male Mice Mice, Knockout Mice, Nude Stomach Neoplasms / drug therapy* Stomach Neoplasms / pathology Tumor Suppressor Protein p53 / genetics |
| IF | 5.791 |
| 引用数 | 3 |
| リソース情報 | |
| ヒト・動物細胞 | MKN74(RCB1002) MKN7(RCB0999) MKN45(RCB1001) Kato III(RCB2088) |