Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7β-hydroxycholesterol on glioma cells - Université de Lorraine Accéder directement au contenu
Article Dans Une Revue Journal of Steroid Biochemistry and Molecular Biology Année : 2019

Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7β-hydroxycholesterol on glioma cells

Résumé

Steroidal maleic anhydrides were prepared in one step: lithocholic, chenodeoxicholic, deoxicholic, ursocholic, and hyodeoxicholic acid derivatives. Their capability to induce cell death was studied on C6 rat glioma cells, and 7β-hydroxycholesterol was used as positive cytotoxic control. The highest cytotoxicity was observed with lithocholic and chenodeoxicholic acid derivatives (23-(4-methylfuran-2,5-dione)-3α-hydroxy-24-nor-5β- cholane (compound 1a), and 23-(4-methylfuran-2,5-dione)-3α,7α-dihydroxy-24-nor-5β- cholane (compound 1b), respectively), which induce a non-apoptotic mode of cell death associated with mitochondrial membrane potential loss and reactive oxygen species overproduction. No cells with condensed and/or fragmented nuclei, no PARP degradation and no cleaved-caspase-3, which are apoptotic criteria, were observed. Similar effects were found with 7β-hydroxycholesterol. The cell clonogenic survival assay showed that compound 1b was more cytotoxic than compound 1a and 7β-hydroxycholesterol. Compound 1b and 7β- hydroxycholesterol also induce cell cycle modifications. In addition, compounds 1a and 1b, and 7β-hydroxycholesterol favour the formation of large acidic vacuoles revealed by staining with acridine orange and monodansylcadaverine evocating autophagic vacuoles; they also induce an increased ratio of [LC3-II / LC3-I], and modify the expression of mTOR, Beclin-1, Atg12, and Atg5-Atg12 which is are autophagic criteria. The ratio [LC3-II / LC3-I] is also strongly modified by bafilomycin acting on the autophagic flux. Rapamycin, an autophagic inducer, and 3-methyladenine, an autophagic inhibitor, reduce and increase 7β- hydroxycholesterol-induced cell death, respectively, supporting that 7β-hydroxycholesterol induces survival autophagy. Alpha-tocopherol also strongly attenuates 7β-hydroxycholesterol- induced cell death. However, rapamycin, 3-methyladenine, and α-tocopherol have no effect on compounds 1a and 1b-induced cell death. It is concluded that these compounds trigger a non apoptotic mode of cell death, involving the mitochondria and associated with several characteristics of autophagy.
Fichier principal
Vignette du fichier
S0960076019300445.pdf (3.52 Mo) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03485843 , version 1 (20-12-2021)

Licence

Paternité - Pas d'utilisation commerciale

Identifiants

Citer

K. Sassi, T. Nury, A. Zarrouk, R. Sghaier, A. Khalafi-Nezhad, et al.. Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7β-hydroxycholesterol on glioma cells. Journal of Steroid Biochemistry and Molecular Biology, 2019, 191, pp.105371. ⟨10.1016/j.jsbmb.2019.04.020⟩. ⟨hal-03485843⟩
18 Consultations
30 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More