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GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma.
- Source :
- Investigational New Drugs; Dec2019, Vol. 37 Issue 6, p1135-1145, 11p
- Publication Year :
- 2019
-
Abstract
- Summary: 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 (IC<subscript>50</subscript> of 1.5 ± 0.2 μM in HuCCT1 and IC<subscript>50</subscript> 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 01676997
- Volume :
- 37
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Investigational New Drugs
- Publication Type :
- Academic Journal
- Accession number :
- 139694275
- Full Text :
- https://doi.org/10.1007/s10637-019-00741-3