Muscarinic Activation Enhances the Anti-proliferative Effect of Paclitaxel in Murine Breast Tumor Cells

Abstract

Muscarinic acetylcholine receptors (mAChR) are expressed in cells without nervous origin. mAChR are up-regulated in tumor cells and their stimulation can modulate tumor growth. In this work we investigated the ability of mAChR activation to induce tumor cell death. We studied the action of a combination of low doses of the muscarinic agonist carbachol plus paclitaxel, a chemotherapeutic agent frequently used in breast cancer treatment, in terms of effectiveness. Long term treatment with carbachol exerted anti-proliferative actions on LM2 and LM3 murine mammary adenocarcinoma cells, similarly to paclitaxel. The combination of carbachol with paclitaxel at submaximal concentrations, added during 20 h decreased tumor cell proliferation in a more potent manner than each drug added separately. This effect was reverted by the muscarinic antagonist atropine, and was due to a potentiation of tumor cell apoptosis tested by TUNEL assay. This treatment did not affect the proliferation of the non tumorigenic mammary cell line NMuMG. In conclusion, the combination of a muscarinic agonist plus paclitaxel should be tested as a useful therapeutic tool in breast cancer treatment.

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

“…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.…”

“…Their role in the regulation of important cell functions like mitosis, cell morphology, locomotion and immune response which are key steps during tumor progression has been documented [12]. The long-term activation of these receptors with the agonist carbachol stimulates cytotoxicity either in human or in murine breast tumor cells [13,14]. In the last years, several reports demonstrated that the activation of M 2 receptor subtype by a selective agonist was able to arrest cell proliferation in different tumor cell lines [15-17].…”

Role of GABA B receptors and p38MAPK/NF-κB pathway in paclitaxel-induced apoptosis of hippocampal neurons

“…In this study, the exposure time and the optimum concentration of paclitaxel for hippocampal neurons were based on a previous study (Español et al. 2012 ). Our results revealed a reciprocal relationship between concentration and exposure time, which is consistent with results of previous studies on paclitaxel in cancer cells (Chirio et al.…”

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

“…Because of the latter, we performed concentration-response and time-response experiments analyzing LM2 and LM 3 cell viability in the presence of carbachol [17]. We observed that carbacholstimulated cell proliferation when it was added to cell cultures for ≤10 h [60,62]. But if cells were treated with the agonist for longer periods of time (≥10 h) it exerted an inhibitory action on tumor cell viability (LM2: 62±6% and LM3: 56±8%) [62].…”