| 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
|
| リソース情報 |
| ヒト・動物細胞 |
HuCCT1(RCB1960)
RBE(RCB1292) |
