Role of Muscarinic Acetylcholine Receptors in Breast Cancer: Design of Metronomic Chemotherapy

Abstract

Background: muscarinic acetylcholine receptors (mAChRs) have attracted interest as targets for therapeutic interventions in different illnesses like Alzheimer´s disease, viral infections and different tumors. Regarding the latter, many authors have studied each subtype of mAChRs, which seem to be involved in the progression of distinct types of malignancies.

Methods: We carefully revised research literature focused on mAChRs expression and signaling as well as in their involvement in cancer progression and treatment. The characteristics of screened papers were described using the mentioned conceptual framework.

Results: Muscarinic antagonists and agonists have been assayed for the treatment of tumors established in lung, brain and breast with beneficial effects. We described an up-regulation of mAChRs in mammary tumors and the lack of expression in non-tumorigenic breast cells and normal mammary tissues. We and others demonstrated that muscarinic agonists can trigger anti-tumor actions in a dose-dependent manner on tumors originated in different organs like brain or breast. At pharmacological concentrations, they exert similar effects to traditional chemotherapeutic agents. Metronomic chemotherapy refers to the administration of anti-cancer drugs at low doses with short intervals among them, and it is a different regimen applied in cancer treatment reducing malignant growth and angiogenesis, and very low incidence of adverse effects.

Conclusion: The usage of subthreshold concentrations of muscarinic agonists combined with conventional chemotherapeutic agents could be a promising tool for breast cancer therapy.

Keywords: Muscarinic acetylcholine receptors; acetylcholine (ACh); breast tumors; metronomic chemotherapy; repurposing drugs; signal metabolic pathway..

Fig. (1)

Mechanisms of internalization and degradation/recycling of muscarinic (M) receptors in a clathrin-dependent or -independent pathway. The binding of acetylcholine (ACh) to different M subtypes besides triggering M receptors signaling leads to the activation of β-arrestins and the recycling of receptors by two different mechanisms. G-protein receptor kinases (GRK); ADP-ribosylation factor 6 (ARF6); GTPase activating protein (GAP). (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Action of a muscarinic agonists on breast tumor cells. The addition of the nuscarinic agonist carbachol (Carb) for a short time (1 h or less) exerts stimulatory actions on muscarinic receptors expressed in tumor cells promoting proliferation invasion and angiogenesis. When Carb or arecaidine propargyl ester (APE) is added for longer periods of time to tumor cell cultures it produces cytotoxicity in a concentration dependent-manner increasing either necrosis or apoptosis. Finally if Carb or APE is added together with paclitaxel (PX) both at subthreshold concentrations they increase cell death favoring apoptosis and anti-angiogenesis. (A higher resolution / colour version of this figure is available in the electronic copy of the article).