التفاصيل البيبلوغرافية
| العنوان: |
GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions |
| المؤلفون: |
Sonia Brun (328449), Eloïne Bestion (8409300), Eric Raymond (777101), Firas Bassissi (9135105), Zuzana Macek Jilkova (9135087), Soraya Mezouar (6817880), Madani Rachid (9135108), Marie Novello (9135090), Jennifer Tracz (489960), Ahmed Hamaï (216991), Gilles Lalmanach (142245), Lise Vanderlynden (9135099), Raphael Legouffe (116862), Jonathan Stauber (116864), Thomas Schubert (394821), Maximilian G. Plach (11656192), Jérôme Courcambeck (2694580), Cyrille Drouot (11656195), Guillaume Jacquemot (2047276), Cindy Serdjebi (788106), Gael Roth (11656198), Jean-Pierre Baudoin (278550), Christelle Ansaldi (9135111), Thomas Decaens (6291578), Philippe Halfon (38086) |
| سنة النشر: |
2021 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Biophysics, Biochemistry, Cell Biology, Pharmacology, Biotechnology, Cancer, Biological Sciences not elsewhere classified, Chemical Sciences not elsewhere classified, Physical Sciences not elsewhere classified, Antitumor, autophagy, liver cancer, lysosome, mtor, PPT1 |
| الوصف: |
Hepatocellular carcinoma is the most frequent primary liver cancer. Macroautophagy/autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two hepatocellular carcinoma in vivo models. We showed that due to its lysosomotropic properties, GNS561 could reach and specifically inhibited its enzyme target, PPT1 (palmitoyl-protein thioesterase 1), resulting in lysosomal unbound Zn 2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of MTOR (mechanistic target of rapamycin kinase), lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, for which a global phase 1b clinical trial in liver cancers was just successfully achieved, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment. Abbreviations : ANXA5:annexin A5; ATCC: American type culture collection; BafA1: bafilomycin A 1 ; BSA: bovine serum albumin; CASP3: caspase 3; CASP7: caspase 7; CASP8: caspase 8; CCND1: cyclin D1; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; CQ: chloroquine; iCCA: intrahepatic cholangiocarcinoma; DEN: diethylnitrosamine; DMEM: Dulbelcco’s modified Eagle medium; FBS: fetal bovine serum; FITC: fluorescein isothiocyanate; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCC: hepatocellular carcinoma; HCQ: hydroxychloroquine; HDSF: hexadecylsulfonylfluoride; IC 50 : mean half-maximal inhibitory concentration; LAMP: lysosomal associated membrane protein; LC3-II: phosphatidylethanolamine-conjugated form of MAP1LC3; LMP: lysosomal membrane permeabilization; MALDI: matrix assisted laser desorption ionization; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
unknown |
| العلاقة: |
https://figshare.com/articles/journal_contribution/GNS561_a_clinical-stage_PPT1_inhibitor_is_efficient_against_hepatocellular_carcinoma_i_via_i_modulation_of_lysosomal_functions/16943749Test |
| DOI: |
10.6084/m9.figshare.16943749.v1 |
| الإتاحة: |
https://doi.org/10.6084/m9.figshare.16943749.v1Test |
| حقوق: |
CC BY 4.0 |
| رقم الانضمام: |
edsbas.170584BF |
| قاعدة البيانات: |
BASE |
