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GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma

  • Sonia BrunEmail author
  • Firas Bassissi
  • Cindy Serdjebi
  • Marie Novello
  • Jennifer Tracz
  • François Autelitano
  • Marie Guillemot
  • Philippe Fabre
  • Jérôme Courcambeck
  • Christelle Ansaldi
  • Eric Raymond
  • Philipe Halfon
PRECLINICAL STUDIES

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 (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.

Keywords

GNS561 Cholangiocarcinoma Anticancer Lysosome Apoptosis 

Notes

Acknowledgements

The authors are very grateful to Dr. Emilien Dosda, Dr. Xavier Rousset and Sylvain Roveda from Inovotion for their work on the CAM study.

Funding

This study was supported by private funding.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest and consent to the submission of this manuscript.

Ethical approval

According to the French legislation, no ethical approval is needed for scientific experimentations using oviparous embryos (decree n° 2013–118, February 1, 2013; art. R-214–88).

Informed consent

For this type of study, formal consent is not required. This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

10637_2019_741_MOESM1_ESM.pdf (373 kb)
ESM 1 (PDF 373 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sonia Brun
    • 1
    Email author
  • Firas Bassissi
    • 1
  • Cindy Serdjebi
    • 1
  • Marie Novello
    • 1
  • Jennifer Tracz
    • 1
  • François Autelitano
    • 2
  • Marie Guillemot
    • 2
  • Philippe Fabre
    • 2
  • Jérôme Courcambeck
    • 1
  • Christelle Ansaldi
    • 1
  • Eric Raymond
    • 1
    • 3
  • Philipe Halfon
    • 1
  1. 1.Genoscience PharmaMarseilleFrance
  2. 2.Biomarker Discovery DepartmentEvotec SASToulouseFrance
  3. 3.Department of OncologyHôpital Paris Saint JosephParisFrance

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