Cytotoxic and genotoxic effects mediated by M2 muscarinic receptor activation in human glioblastoma cells

Bari, María Di; Tombolillo, Vanessa; Conte, Claudia; Castigli, Emila; Sciaccaluga, Miriam; Iorio, Egidio; Carpinelli, G.; Ricordy, R.; Fiore, Mario; Degrassi, Francesca; Tata, Ada Maria

doi:10.1016/j.neuint.2015.09.008

Cited by 20 publications

(38 citation statements)

References 36 publications

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“…However, in hypoxia, M2 agonist caused a progressive accumulation in M phase, causing aberrant mitosis. This result is in accordance with previous results obtained in GBM cells demonstrating the ability of Ape to induce genotoxic and cytotoxic effects that could well correlate with DNA damage and altered cells ability to divide correctly [19]. This aspect may be significantly increased in GB7 cells by the hypoxic condition and by the downregulation of hypoxic stress regulatory factors such as miR-210 and progranulin (Figure 8).…”

Section: Discussionsupporting

confidence: 92%

“…Conversely, our previous studies have shown that M2 receptors activation by arecaidine propargyl ester (Ape) is able to arrest cell proliferation in GBM cell lines (U87MG and U251MG) and GSCs (GB7 and GB8 cells) [16][17][18]. Moreover, M2 receptor activation induces oxidative stress and severe apoptosis, significantly reducing cell survival in particular in GBM-p53 mutated [19].…”

Section: Introductionmentioning

confidence: 94%

“…Previous studies reported the ability of Ape to negatively modulate cell survival in GBM cell lines [17,19]. In order to evaluate the effects of hypoxia and Ape on GSCs cell survival, we investigated by FACS analysis and propidium iodide staining, the fraction of cells in the sub-G1 phase both in normoxia and hypoxia and upon M2 agonist treatment.…”

Section: M2 Receptors Activation Impairs Gscs Cell Survivalmentioning

confidence: 99%

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M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

Cristofaro

Limongi

Crestini

et al. 2020

IJMS

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Glioblastoma multiforme (GBM) is the most malignant brain tumor. Hypoxic condition is a predominant feature of the GBM contributing to tumor growth and resistance to conventional therapies. Hence, the identification of drugs able to impair GBM malignancy and aggressiveness is considered of great clinical relevance. Previously, we demonstrated that the activation of M2 muscarinic receptors, through the agonist arecaidine propargyl ester (Ape), arrests cell proliferation in GBM cancer stem cells (GSCs). In the present work, we have characterized the response of GSCs to hypoxic condition showing an upregulation of hypoxia-inducible factors and factors involved in the regulation of GSCs survival and proliferation. Ape treatment in hypoxic conditions is however able to inhibit cell cycle progression, causing a significant increase of aberrant mitosis with consequent decreased cell survival. Additionally, qRT-PCR analysis suggest that Ape downregulates the expression of stemness markers and miR-210 levels, one of the main regulators of the responses to hypoxic condition in different tumor types. Our data demonstrate that Ape impairs the GSCs proliferation and survival also in hypoxic condition, negatively modulating the adaptive response of GSCs to hypoxia.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 94%

Section: M2 Receptors Activation Impairs Gscs Cell Survivalmentioning

confidence: 99%

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M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

Cristofaro

Limongi

Crestini

et al. 2020

IJMS

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“…The participation of this receptor subtype was confirmed by reversing the effect either with the preferential selective M 2 antagonist methoctramine. In line with our findings, similar effects were demonstrated in human glioblastoma cell lines and in glioblastoma cancer stem cells [16,17]. As it can be seen from the results obtained in the current work, the presence of M 2 receptors could be useful to target them with metronomic therapy in TN breast cancer treatment.…”

Section: Discussionsupporting

confidence: 91%

“…We also observed that the long term addition either of carbachol or APE (non-selective and M 2 receptor selective agonists, respectively) reduced cell viability in these breast tumor cells. Previous results from our group and also from other authors pointed to the ability of these muscarinic agonists to produce cell death in murine breast, bladder and neuronal tumor cells [14-16]. These results let us consider muscarinic receptors as specific therapeutic targets for the treatment of TN breast tumors since they are classified as very aggressive and malignant.…”

Section: Discussionsupporting

confidence: 64%

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M₂receptor subtype

Español

Salem

Bari

et al. 2019

Preprint

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35Triple negative tumors are more aggressive than other breast cancer subtypes 36 and there is a lack of specific therapeutic targets on them. Since muscarinic receptors 37 have been linked to tumor progression, we investigated the effect of metronomic 38 therapy employing a traditional anti-cancer drug, paclitaxel plus muscarinic agonists at 39 low doses on this type of tumor. We observed that MDA-MB231 tumor cells express 40 muscarinic receptors, while they are absent in the non-tumorigenic MCF-10A cell line, 41 which was used as control. The addition of carbachol or arecaidine propargyl ester, a 42 non-selective or a selective subtype 2 muscarinic (M 2 ) receptor agonist respectively, 43 plus paclitaxel reduces cell viability involving a down-regulation in the expression of 44 ATP "binding cassette" G2 drug transporter and epidermal growth factor receptor. We 45 also detected an inhibition of tumor cell migration and anti-angiogenic effects produced 46 by those drug combinations in vitro and in vivo (in NUDE mice) respectively. Our 47 findings provide substantial evidence about M 2 receptors as therapeutic target for the 48 treatment of triple negative tumors. 49 50 51 Breast cancer is yet the most frequent type of malignancy in women and 52 represents a major and unsolved problem for public health [1]. Luminal and triple 53 negative (TN) represent the two opposite ends of the molecular classification of breast 54 tumors and they thoroughly differ regarding treatment and patients´survival [2]. The TN 55 tumors are typically larger in size, higher grade than other breast cancers, and they also 56 exhibit an aggressive clinical behavior, frequently resulting in early metastatic 57 dissemination, particularly to visceral sites. As a result of these characteristics, TN 58 breast cancers are associated with poor prognosis in comparison to luminal breast 59 tumors [3]. Considering the treatment of TN tumors, classical modalities have improved 60 the overall outlook and quality of life for women with this type of breast cancer.61However, because of recurrence and/or the development of resistance to cytotoxic drugs 62 administered to patients, produced by a complex mechanism mediated by different types 63 of proteins such as ATP "binding cassette" (ABC) transporters, a considerable amount 64 of patients still succumb to this disease highlighting the need to find new therapeutic 65 approaches [4]. Regarding the latter, the usage of low dose chemotherapy with short 66 drug free intervals, named metronomic therapy has emerged as a novel regimen for 67 cancer treatment [5]. It exerts very low incidence of side effects and could add new 3 68 beneficial actions on immune system and tumor microenvironment [6]. This new 69 strategy also needs the identification of new therapeutic targets to improve the benefits 70 for breast cancer patients. 71 Non-neuronal cholinergic system (nNCS) has been involved either in 72 physiological or in pathological processes. The nNCS is formed by acethylcholyne 73 (ACh), the enzymes...

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The activation of M2 muscarinic receptor inhibits cell growth and survival in human epithelial ovarian carcinoma

Taggi

Kovacevic

Capponi

et al. 2022

J of Cellular Biochemistry

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Ovarian cancer is the fifth leading cause of cancer-related deaths in females.Many ovarian tumor cell lines express muscarinic receptors (mAChRs), and their expression is correlated with reduced survival of patients. We have characterized the expression of mAChRs in two human ovarian carcinoma cell lines (SKOV-3, TOV-21G) and two immortalized ovarian surface epithelium cell lines (iOSE-120, iOSE-398). Among the five subtypes of mAChRs (M1-M5 receptors), we focused our attention on the M2 receptor, which is involved in the inhibition of tumor cell proliferation. Western blot analysis and real-time PCR analyses indicated that the levels of M2 are statistically downregulated in cancer cells. Therefore, we investigated the effect of arecaidine propargyl ester hydrobromide (APE), a preferential M2 agonist, on cell growth and survival. APE treatment decreased cell number in a dose and time-dependent manner by decreasing cell proliferation and increasing cell death. FACS and immunocytochemistry analysis have also demonstrated the ability of APE to accumulate the cells in G2/M phase of the cell cycle and to increase the percentage of abnormal mitosis. The higher level of M2 receptors in the iOSE cells rendered these cells more sensitive to APE treatment than cancer cells.The data here reported suggest that M2 has a negative role in cell growth/ survival of ovarian cell lines, and its downregulation may favor tumor progression.

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Cytotoxic and genotoxic effects mediated by M2 muscarinic receptor activation in human glioblastoma cells

Cited by 20 publications

References 36 publications

M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M₂receptor subtype

The activation of M2 muscarinic receptor inhibits cell growth and survival in human epithelial ovarian carcinoma

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Cytotoxic and genotoxic effects mediated by M2 muscarinic receptor activation in human glioblastoma cells

Cited by 20 publications

References 36 publications

M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

M2 Receptor Activation Counteracts the Glioblastoma Cancer Stem Cell Response to Hypoxia Condition

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2receptor subtype

The activation of M2 muscarinic receptor inhibits cell growth and survival in human epithelial ovarian carcinoma

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The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M₂receptor subtype