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.

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

“…The production of ACh by tumor cells and the subsequent interaction with muscarinic receptors frequently activate an autocrine/paracrine loop, modulating cell proliferation, migration and angiogenesis [ 23 ]. Several studies have largely reported the involvement of muscarinic receptors in several primary and metastatic tumors, such as colon [ 24 , 25 ], ovary [ 26 ], prostate [ 27 , 28 , 29 ], lung [ 30 , 31 ] and breast carcinoma [ 32 , 33 , 34 , 35 ], melanoma [ 36 ] and in glioblastoma, as demonstrated by our group [ 37 , 38 , 39 , 40 , 41 , 42 ].…”

The metronomic combination of paclitaxel with cholinergic agonists inhibits triple negative breast tumor progression. Participation of M2 receptor subtype

“…Considering the latter, together with our previous findings in MCF-7 cells that were sensible to a low dose metronomic therapy focused on muscarinic receptors [16] we designed a metronomic administration of PX plus muscarinic agonists at low concentrations. This strategy, besides focusing on muscarinic receptors as novel targets for the treatment of TN tumors, could be less aggressive for normal mammary cells that lack of these receptors [2,12]. Moreover, our results reveal the possibility of generalizing the usage of this combination of drugs since it is also effective when PX is replaced by doxorubicin.…”

“…Breast cancer is still the most frequent type of malignancy in women and represents a major and unsolved problem for public health [ 1 , 2 ]. Luminal and triple negative (TN) represent the two opposite ends of the molecular classification of breast tumors and they thoroughly differ regarding treatment and patients´survival [ 3 ].…”

Important players in carcinogenesis as potential targets in cancer therapy: an update

“…One of the factors involved in the carcinogenesis process is acetylcholine and its receptors, both muscarinic and nicotinic. Their expression has been demonstrated in numerous types of cancer cells [19][20][21]. It has also been proven that these cells contain acetylcholinesterase (AChE), an enzyme that enables cells to produce ACh in the absence of agonists from the external environment.…”