The synthetic flavagline FL3 spares normal human skin cells from its cytotoxic effect via an activation of Bad. (October 2019)

• Record Type: Journal Article
• Authors: Emhemmed, Fathi; Azouaou, Sarah Ali; Hassan, Sarah; Lefevbre, Ray; Désaubry, Laurent; Muller, Christian D.; Fuhrmann, Guy
• Is Part Of: Toxicology in vitro. Volume 60(2019)
• Page Start: 27
• Page End: 35
• Publication Date: 2019-10
• Subjects: Flavagline -- Normal skin cell -- Cytotoxicity -- Resistance -- Bad phosphorylation; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2019.04.025
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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. Graphical abstract: Unlabelled Image Highlights: The synthetic flavagline FL3 selectively kills cancer cells, without having any effect on normal cells. FL3 specifically induces the activation of Bcl-2-associated death promoter protein (Bad) in normal skin cells. Knock-down of Bad removes the protection of normal skin cells against the cytotoxic effect of FL3. The resistance of normal cells against FL3 cytotoxicity identifies it as a promising drug for an elective anticancer therapy.