The synthetic flavagline FL3 spares normal human skin cells from its cytotoxic effect via an activation of Bad.
Fiche publication
Date publication
avril 2019
Journal
Toxicology in vitro : an international journal published in association with BIBRA
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DESAUBRY Laurent, Dr MULLER Christian, Dr FUHRMANN Guy
Tous les auteurs :
Emhemmed F, Azouaou SA, Hassan S, Lefevbre R, Désaubry L, Muller CD, Fuhrmann G
Lien Pubmed
Résumé
The molecular pathways by which flavagline derivatives exert their cytotoxicity against various cancer cell types are well documented, while the mechanisms that prevent their cytotoxic effects on normal cells still have to be clarified. Here we provide the underlying molecular events by which normal skin cells remain unaffected after exposure to the synthetic flavagline FL3. Indeed, the anticancer agent fails to trigger apoptosis of healthy cells and is unable to induce the depolarization of their mitochondrial membrane and the cytosolic release of cytochrome C, in contrast to what is observed for cancer cells. Most importantly, FL3 specifically induces in normal cells, but not in malignant cells, an activation of Bad, without significant mitochondrial and cytosolic redistribution of Bax or Bcl-2. Moreover, gene knockdown of Bad sensitizes the normal fibroblastic cells to FL3 and induces a caspase-3 dependent apoptosis. Bad activation, known to promote survival and block apoptosis, explains therefore the lack of cytotoxicity of FL3 on normal skin cells. Finally, these findings provide new insights into the molecular mechanisms of resistance of healthy cells against FL3 cytotoxicity and identify it as a promising anticancer drug.
Mots clés
Bad phosphorylation, Cytotoxicity, Flavagline, Normal skin cell, Resistance
Référence
Toxicol In Vitro. 2019 Apr 24;: