Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells. (September 2018)

• Record Type: Journal Article
• Authors: Cristofaro, Ilaria; Spinello, Zaira; Matera, Carlo; Fiore, Mario; Conti, Luciano; De Amici, Marco; Dallanoce, Clelia; Tata, Ada Maria
• Is Part Of: Neurochemistry international. Volume 118(2018)
• Page Start: 52
• Page End: 60
• Publication Date: 2018-09
• Subjects: Cancer stem cells -- Cell death -- M2 muscarinic acetylcholine receptors -- Dualsteric (allosteric/orthosteric) activators -- DNA damage; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2018.04.010
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: In previous studies, we found that the orthosteric muscarinic agonist arecaidine propargyl ester (APE) (100 μM) induced a decreased cell proliferation and severe apoptosis in glioblastoma cancer stem cells (GSCs). In this report, we have investigated the effects mediated by hybrid (orthosteric/allosteric) muscarinic agonists P-6-Iper and N-8-Iper on GSCs survival. At variance with APE, the agonist N-8-Iper inhibited cell growth in a dose dependent manner and also impaired cell survival at low doses. The inhibitory effects of the N-8-Iper action appear to be mediated by M2 receptor activation, since they were strongly reduced by co-administration of the selective M2 receptor antagonist methoctramine as well as upon M2 receptor silencing. Moreover, analysis of the expression of phosphorylated histone H2AX (γ-H2AX) indicated that the treatment with N-8-Iper produced a decreased cell survival by induction of DNA damage. The ability of N-8-Iper to produce a cytotoxic effect and apoptosis at low doses indicates that this muscarinic agonist is a suitable probe in a putative therapeutic intervention on glioblastoma through M2 receptor activation. Graphical abstract: Highlights: Dualsteric muscarinic agonist N-8-Iper showed cytotoxic effects in GSCs. N-8-Iper inhibited cell growth in a dose dependent manner and caused a decreased cell survival by induction of DNA damage. The effects of N-8-Iper are mediated by M2 receptor activation. M2 activators result promising therapeutic agents for glioblastoma therapy.