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Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress

Authors :
Juliette Humeau
Allan Sauvat
Giulia Cerrato
Wei Xie
Friedemann Loos
Francesca Iannantuoni
Lucillia Bezu
Sarah Lévesque
Juliette Paillet
Jonathan Pol
Marion Leduc
Laurence Zitvogel
Hugues de Thé
Oliver Kepp
Guido Kroemer
Source :
EMBO Molecular Medicine, Vol 12, Iss 5, Pp 1-22 (2020)
Publication Year :
2020
Publisher :
Springer Nature, 2020.

Abstract

Abstract Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre‐mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long‐term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune‐dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm‐selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction.

Details

Language :
English
ISSN :
20191162, 17574676, and 17574684
Volume :
12
Issue :
5
Database :
Directory of Open Access Journals
Journal :
EMBO Molecular Medicine
Publication Type :
Academic Journal
Accession number :
edsdoj.9ac05f98dda3489daa122aa6f33d4ae1
Document Type :
article
Full Text :
https://doi.org/10.15252/emmm.201911622