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Fraisinib: a calixpyrrole derivative reducing A549 cell-derived NSCLC tumor in vivo acts as a ligand of the glycine-tRNA synthase, a new molecular target in oncology

Authors :
Iméne Ben Toumia
Tiziana Bachetti
Leila Chekir-Ghedira
Aldo Profumo
Marco Ponassi
Alessandro Di Domizio
Alberto Izzotti
Salvatore Sciacca
Caterina Puglisi
Stefano Forte
Raffaella Giuffrida
Cristina Colarossi
Danilo Milardi
Giuseppe Grasso
Valeria Lanza
Stefano Fiordoro
Giacomo Drago
Kateryna Tkachenko
Barbara Cardinali
Paolo Romano
Erika Iervasi
Gabriela Coronel Vargas
Paola Barboro
Franz Heinrich Kohnke
Camillo Rosano
Source :
Frontiers in Pharmacology, Vol 14 (2024)
Publication Year :
2024
Publisher :
Frontiers Media S.A., 2024.

Abstract

Background and purpose: Lung cancer is the leading cause of death in both men and women, constituting a major public health problem worldwide. Non-small-cell lung cancer accounts for 85%–90% of all lung cancers. We propose a compound that successfully fights tumor growth in vivo by targeting the enzyme GARS1.Experimental approach: We present an in-depth investigation of the mechanism through which Fraisinib [meso-(p-acetamidophenyl)-calix(4)pyrrole] affects the human lung adenocarcinoma A549 cell line. In a xenografted model of non-small-cell lung cancer, Fraisinib was found to reduce tumor mass volume without affecting the vital parameters or body weight of mice. Through a computational approach, we uncovered that glycyl-tRNA synthetase is its molecular target. Differential proteomics analysis further confirmed that pathways regulated by Fraisinib are consistent with glycyl-tRNA synthetase inhibition.Key results: Fraisinib displays a strong anti-tumoral potential coupled with limited toxicity in mice. Glycyl-tRNA synthetase has been identified and validated as a protein target of this compound. By inhibiting GARS1, Fraisinib modulates different key biological processes involved in tumoral growth, aggressiveness, and invasiveness.Conclusion and implications: The overall results indicate that Fraisinib is a powerful inhibitor of non-small-cell lung cancer growth by exerting its action on the enzyme GARS1 while displaying marginal toxicity in animal models. Together with the proven ability of this compound to cross the blood–brain barrier, we can assess that Fraisinib can kill two birds with one stone: targeting the primary tumor and its metastases “in one shot.” Taken together, we suggest that inhibiting GARS1 expression and/or GARS1 enzymatic activity may be innovative molecular targets for cancer treatment.

Details

Language :
English
ISSN :
16639812
Volume :
14
Database :
Directory of Open Access Journals
Journal :
Frontiers in Pharmacology
Publication Type :
Academic Journal
Accession number :
edsdoj.6ffba98dfa4c89a608a26bff651fbc
Document Type :
article
Full Text :
https://doi.org/10.3389/fphar.2023.1258108