期刊
CANCERS
卷 12, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/cancers12061621
关键词
Lysosome; lysosomal membrane permeabilization; cell death; cancer; G-quadruplex ligand; triarylpyridine compounds; resistance to therapy
类别
资金
- Ligue Regionale d'Aquitaine, comite de Dordogne
- SIRIC BRIO
- FR Transbiomed
- Ligue Regionale d'Aquitaine
- Mexican National Council of Science and Technology (CONACYT) [757821]
- Ligue contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR) -Projets blancs
- ANR
- ANR Flash-covid-19 LYSOMOTROP
- ERA-Net for Research on Rare Diseases
- AMMICa US23/CNRS UMS3655
- Association pour la recherche sur le cancer (ARC)
- Association Le Cancer du Sein, Parlons-en!
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix), Fondation pour la Recherche Medicale (FRM)
- Gustave Roussy Odyssea
- European Union Horizon 2020 Project Oncobiome
- Fondation Carrefour
- High-end Foreign Expert Program in China [GDW20171100085]
- Institut National du Cancer (INCa)
- Inserm (HTE)
- Institut Universitaire de France
- LeDucq Foundation
- LabEx Immuno-Oncology [ANR-18-IDEX-0001]
- RHU Torino Lumiere
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR)
Lysosomes play a key role in regulating cell death in response to cancer therapies, yet little is known on the possible role of lysosomes in the therapeutic efficacy of G-quadruplex DNA ligands (G4L) in cancer cells. Here, we investigate the relationship between the modulation of lysosomal membrane damage and the degree to which cancer cells respond to the cytotoxic effects of G-quadruplex ligands belonging to the triarylpyridine family. Our results reveal that the lead compound of this family,20Apromotes the enlargement of the lysosome compartment as well as the induction of lysosome-relevant mRNAs. Interestingly, the combination of20Aand chloroquine (an inhibitor of lysosomal functions) led to a significant induction of lysosomal membrane permeabilization coupled to massive cell death. Similar effects were observed when chloroquine was added to three new triarylpyridine derivatives. Our findings thus uncover the lysosomal effects of triarylpyridines compounds and delineate a rationale for combining these compounds with chloroquine to increase their anticancer effects.
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