Title : GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma - Brun_2019_Invest.New.Drugs_37_1135 |
Author(s) : Brun S , Bassissi F , Serdjebi C , Novello M , Tracz J , Autelitano F , Guillemot M , Fabre P , Courcambeck J , Ansaldi C , Raymond E , Halfon P |
Ref : Invest New Drugs , 37 :1135 , 2019 |
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 (IC(50) of 1.5 +/- 0.2 microM in HuCCT1 and IC(50) of 1.7 +/- 0.1 microM 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. |
PubMedSearch : Brun_2019_Invest.New.Drugs_37_1135 |
PubMedID: 30778887 |
Inhibitor | Ezurpimtrostat |
Brun S, Bassissi F, Serdjebi C, Novello M, Tracz J, Autelitano F, Guillemot M, Fabre P, Courcambeck J, Ansaldi C, Raymond E, Halfon P (2019)
GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma
Invest New Drugs
37 :1135
Brun S, Bassissi F, Serdjebi C, Novello M, Tracz J, Autelitano F, Guillemot M, Fabre P, Courcambeck J, Ansaldi C, Raymond E, Halfon P (2019)
Invest New Drugs
37 :1135