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

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.

• Authors: Ilaria Cristofaro, Zaira Spinello, Carlo Matera, Mario Fiore, Luciano Conti, Marco De Amici, Clelia Dallanoce, Ada Maria Tata
• Journal: Neurochemistry international (Neurochem Int) Vol. 118 Pg. 52-60 (09 2018) ISSN: 1872-9754 [Electronic] England
• PMID: 29702145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Muscarinic Agonists
• Receptor, Muscarinic M2

Topics

• Cell Line, Tumor
• Cell Survival (drug effects, physiology)
• DNA Damage (drug effects, physiology)
• Dose-Response Relationship, Drug
• Glioblastoma (pathology)
• Humans
• Muscarinic Agonists (pharmacology)
• Neoplastic Stem Cells (drug effects, pathology)
• Receptor, Muscarinic M2 (agonists, metabolism)