Effects mediated by M2 muscarinic orthosteric agonist on cell growth in human neuroblastoma cell lines

Luciano, A.; Mattei, Francesca Romana; Damo, Elisa; Panzarini, Elisa; Dini, Luciana; Tata, Ada Maria

doi:10.1515/pac-2018-1224

Cited by 6 publications

(11 citation statements)

References 21 publications

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“…Moreover, the contribution of muscarinic receptors in tumor progression has also been demonstrated and the use of agonists or antagonists for different cholinergic receptor subtypes is emerging as therapy for different pathologies [11,[26][27][28]. Previously it has been demonstrated the ability of M2 receptor to counteract tumor cell growth and survival both in GBM and in GSCs [16][17][18][19], in neuroblastoma [29] and in urothelial bladder cells [30].…”

Section: Discussionmentioning

confidence: 99%

Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival

Cristofaro

Alessandrini

Spinello

et al. 2020

Cells

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Glioblastomas (GBM) are the most aggressive form of primary brain tumors in humans. A key feature of malignant gliomas is their cellular heterogeneity. In particular, the presence of an undifferentiated cell population of defined Glioblastoma Stem cells (GSCs) was reported. Increased expression of anti-apoptotic and chemo-resistance genes in GCSs subpopulation favors their high resistance to a broad spectrum of drugs. Our previous studies showed the ability of M2 muscarinic receptors to negatively modulate the cell growth in GBM cell lines and in the GSCs. The aim of this study was to better characterize the inhibitory effects of M2 receptors on cell proliferation and survival in GSCs and investigate the molecular mechanisms underlying the M2-mediated cell proliferation arrest and decreased survival. Moreover, we also evaluated the ability of M2 receptors to interfere with Notch1 and EGFR pathways, whose activation promotes GSCs proliferation. Our data demonstrate that M2 receptors activation impairs cell cycle progression and survival in the primary GSC lines analyzed (GB7 and GB8). Moreover, we also demonstrated the ability of M2 receptor to inhibit Notch1 and EGFR expression, highlighting a molecular interaction between M2 receptor and the Notch-1/EGFR pathways also in GSCs.

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Section: Discussionmentioning

confidence: 99%

Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival

Cristofaro

Alessandrini

Spinello

et al. 2020

Cells

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“…Moreover, in neuroblastoma and glioblastoma cell lines, we have also demonstrated that M1 and M3 antagonists, pirenzepine and 4-DAMP, respectively, were not able to counteract APE effects, confirming preferential selectivity of APE for M2 receptor. Moreover, after M2 knockdown by short interference RNA, APE effect was completely abolished [ 16 , 29 , 30 , 31 ]. Finally, it is relevant to note that M4 receptor expression both in rat [ 9 ] and in hSCs appears significantly lower than M2 subtype, at least at transcript level; for this reason, the potential interference of M4 receptors, should be irrelevant.…”

Section: Discussionmentioning

confidence: 99%

“…Our works have been focused on the characterization of APE hydrobromide by pharmacological competition studies with M2 antagonists methoctramine or gallamine [ 8 , 17 , 32 ]. Moreover, the silencing of M2 receptors by siRNAs have largely demonstrated the selectivity of APE for M2 receptor in several cell lines (i.e., human glioblastoma, neuroblastoma, and urothelial bladder cell lines [ 16 , 29 , 30 , 31 , 33 ].…”

Section: Methodsmentioning

confidence: 99%

Functional Characterization of Muscarinic Receptors in Human Schwann Cells

Piovesana

Faroni

Tata

et al. 2020

IJMS

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Functional characterization of muscarinic cholinergic receptors in myelinating glial cells has been well described both in central and peripheral nervous system. Rat Schwann cells (SCs) express different muscarinic receptor subtypes with the prevalence of the M2 subtype. The selective stimulation of this receptor subtype inhibits SC proliferation, improving their differentiation towards myelinating phenotype. In this work, we describe for the first time that human SCs are cholinoceptive as they express several muscarinic receptor subtypes and, as for rat SCs, M2 receptor is one of the most abundant. Human SCs, isolated from adult nerves, were cultured in vitro and stimulated with M2 muscarinic agonist arecaidine propargyl ester (APE). Similarly to that observed in rat, M2 receptor activation causes a decreased cell proliferation and promotes SC differentiation as suggested by increased Egr2 expression with an improved spindle-like shape cell morphology. Conversely, the non-selective stimulation of muscarinic receptors appears to promote cell proliferation with a reduction of SC average cell diameter. The data obtained demonstrate that human SCs are cholinoceptive and that human cultured SCs may represent an interesting tool to understand their physiology and increase the knowledge on how the cholinergic stimulation may contribute to address human SC development in normal and pathological conditions.

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“…More recently, we expanded this list including neuroblastoma, focusing our attention on the M2 muscarinic receptor subtype [ 43 ]. What stands out within our research is how selective activation of this receptor can counteract cell proliferation and survival.…”

Section: Introductionmentioning

confidence: 99%

“…More specifically, via selective activation with the M2 agonist arecaidine propargyl ester (APE), we have observed an arrest of cell proliferation in a dose-dependent manner both in neuroblastoma and neuroepithelioma cell lines. We found that the effect produced by APE is associated with the selective activation of M2 receptors; in fact, by silencing the M2 sub-type, we observed an abolishment of the effects that APE mediated [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

The Combination of the M2 Muscarinic Receptor Agonist and Chemotherapy Affects Drug Resistance in Neuroblastoma Cells

Luciano

Perciballi

Fiore

et al. 2020

IJMS

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One of the major limits of chemotherapy is depending on the ability of the cancer cells to elude and adapt to different drugs. Recently, we demonstrated how the activation of the M2 muscarinic receptor could impair neuroblastoma cell proliferation. In the present paper, we investigate the possible effects mediated by the preferential M2 receptor agonist arecaidine propargyl ester (APE) on drug resistance in two neuroblastoma cell lines, SK-N-BE and SK-N-BE(2C), a sub-clone presenting drug resistance. In both cell lines, we compare the expression of the M2 receptor and the effects mediated by the M2 agonist APE on cell cycle, demonstrating a decreased percentage of cells in S phase and an accumulation of SK-N-BE cells in G1 phase, while the APE treatment of SK-N-BE(2C) cells induced a block in G2/M phase. The withdrawal of the M2 agonist from the medium shows that only the SK-N-BE(2C) cells are able to rescue cell proliferation. Further, we demonstrate that the co-treatment of low doses of APE with doxorubicin or cisplatin significantly counteracts cell proliferation when compared with the single treatment. Analysis of the expression of ATP-binding cassette (ABC) efflux pumps demonstrates the ability of the M2 agonist to downregulate their expression and that this negative modulation may be dependent on N-MYC decreased expression induced by the M2 agonist. Our data demonstrate that the combined effect of low doses of conventional drugs and the M2 agonist may represent a new promising therapeutic approach in neuroblastoma treatment, in light of its significant impact on drug resistance and the possible reduction in the side effects caused by high doses of chemotherapy drugs.

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Effects mediated by M2 muscarinic orthosteric agonist on cell growth in human neuroblastoma cell lines

Cited by 6 publications

References 21 publications

Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival

Cross Interaction between M2 Muscarinic Receptor and Notch1/EGFR Pathway in Human Glioblastoma Cancer Stem Cells: Effects on Cell Cycle Progression and Survival

Functional Characterization of Muscarinic Receptors in Human Schwann Cells

The Combination of the M2 Muscarinic Receptor Agonist and Chemotherapy Affects Drug Resistance in Neuroblastoma Cells

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