論文 - 詳細
| RRC ID | 54878 |
|---|---|
| 著者 | Brun S, Bassissi F, Serdjebi C, Novello M, Tracz J, Autelitano F, Guillemot M, Fabre P, Courcambeck J, Ansaldi C, Raymond E, Halfon P. |
| タイトル | GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma. |
| ジャーナル | Invest New Drugs |
| Abstract |
Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell viability in two intrahepatic cholangiocarcinoma cell lines (IC50 of 1.5 ± 0.2 μM in HuCCT1 and IC50 of 1.7 ± 0.1 μM in RBE cells) and induced apoptosis as measured by caspases activation. We confirmed that GNS561-mediated cell death was related to its lysosomotropic properties. GNS561 induced lysosomal dysregulation as proven by inhibition of late-stage autophagy and induction of a dose-dependent build-up of enlarged lysosomes. In patient-derived cells, GNS561 was more potent than cisplatin and gemcitabine in 2/5 and 1/5 of the patient-derived cells models, respectively. Moreover, in these models, GNS561 was potent in models with low sensitivity to gemcitabine. GNS561 was also efficient in vivo against a human intrahepatic cholangiocarcinoma cell line in a chicken chorioallantoic membrane xenograft model, with a good tolerance at doses high enough to induce an antitumor effect in this model. In summary, GNS561 is a new lysosomotropic agent, with an anticancer activity against intrahepatic cholangiocarcinoma. Further investigations are currently ongoing to fully elucidate its mechanism of action. |
| 巻・号 | 37(6) |
| ページ | 1135-1145 |
| 公開日 | 2019-12-1 |
| DOI | 10.1007/s10637-019-00741-3 |
| PII | 10.1007/s10637-019-00741-3 |
| PMID | 30778887 |
| MeSH | Animals Antineoplastic Agents / pharmacology* Bile Duct Neoplasms / drug therapy* Bile Duct Neoplasms / metabolism Cell Line, Tumor Cell Survival / drug effects Chick Embryo Cholangiocarcinoma / drug therapy* Cholangiocarcinoma / metabolism Humans Lysosomes / metabolism* |
| IF | 2.663 |
| 引用数 | 3 |
| 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 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 3 |
| 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 | HuCCT1(RCB1960) RBE(RCB1292) |