Send Orders for Reprints to reprints@benthamscience.net Current Molecular Medicine 2014, 14, 1-13 1 1566-5240/14 $58.00+.00 © 2014 Bentham Science Publishers Cholinergic Receptors as Target for Cancer Therapy in a Systems Medicine Perspective P. Russo *,1 , A. Del Bufalo 1 , M. Milic 1,2 , G. Salinaro 1 , M. Fini 3 and A. Cesario 3 1 Laboratory of Systems Approaches and Non Communicable Diseases, IRCCS “San Raffaele Pisana” Via di Valcannuta, 247, I-00166 Rome, Italy 2 Institute for Medical Research and Occupational Health, Ksaverska cesta 2, Zagreb, Croatia 3 Scientific Direction, IRCCS "San Raffaele Pisana", Via di Val Cannuta 247, I-00166 Rome, Italy Abstract: Epithelial cells not innervated by cholinergic neurons express nicotinic and muscarinic acetylcholine (ACh) receptors (nAChR, mAChR). nAChR and mAChR are components of the auto-/paracrine-regulatory loop of non-neuronal ACh release. The cholinergic control of non-neuronal cells may be mediated by different effects (synergistic, additive, or reciprocal) triggered by these receptors. The ionic events (Ca +2 influx) are generated by the ACh-opening of nAChR channels, while the metabolic events by ACh-binding to G-protein- coupled mAChR. Effective inter- and intracellular signaling is crucial for valuable cancer cells proliferation and survival. Depending on cancer cell type, different AChR have been identified. The proliferation of airways epithelial cancer cells and pancreatic cancer cells may be under the control of α7-nAChR and M3-mAChR, while breast cancer cells and colon cancer cells are regulated by α9-nAChR, and M3-mAChR, respectively. In turn, these receptors may activate different pathways (Ras-Raf-1-Erk-AKT) as well as other receptors (β- adrenergicR). nAChR or mAChR antagonists may inhibit cancer growth. Inhibition of M3 by antisense or antagonists (Darifenacin, Tiotropium) reduces lung or colon cancer proliferation, as well as inhibition of α9- nAChR [polyphenol (-)-epigallocatechin-3-gallate] diminishes breast cancer cells growth. α7-nAChR silencing inhibits lung cancer proliferation. Moreover, inhibition of the nAChR-β-adrenergicR pathway (β-blockers) could be also useful. This review will describe the future translational perspectives of cholinergic receptors drug- inhibition in a complex disease such as cancer that poses compelling treatment challenges. Cancer happens as consequence of disease-perturbed molecular networks in relevant organ cells that change during progression. The framework for approaching these challenges is a systems approach. Keywords: ACh, complex disease, drug discovery and development, mAChR, nAChR, systems biology, systems medicine, therapy. 1. INTRODUCTION It has been reported that a complete cholinergic system [Acetylcholine (ACh), binding structures, degradating enzymes, although the background for synthesizing system is unknown] evolved early in the nature [1]. The first experiments were performed in the plant Urtica dioica, member of the nettle genus Urtica (Order: Rosales, Family: Urticaceae) describing a plant reaction after exposure to agonists or antagonists of cholinergic receptors. These observations suggested a role of the cholinergic system in water homeostasis regulation and photosynthesis (experiments in the dark) [1]. Thus, cholinergic system evolved extra neurons and, when more complex animals appeared, it was utilized also by neurons [1, 2]. Nowadays, human cholinergic system has an important part in cellular signaling, both in neuronal and non-neuronal cells and due to its cellular localization, regulates different *Address correspondence to these authors at the Laboratory of Systems Approaches and Non Communicable Diseases, IRCCS “San Raffaele Pisana”, Via di Val Cannuta, 247, I-00166, Rome Italy; Tel: +390652253741; E-mails: patrizia_russo@hotmail.it, patrizia.russo@sanraffaele.it processes [2]. Cholinergic system is essentially based on ACh as mediator. ACh is synthesized from choline and acetylCoA by the choline acetyltransferase (ChAT) enzyme and stored in vesicles through vesicular ACh transporter (VAChT) activity. After release, ACh binds to two distinctive types of receptors, that, according to their binding affinity of two natural substances (nicotine or muscarine), are usually classified in two large categories: nicotinic acetylcholine receptors (nAChR) or muscarinic acetylcholine receptors (mAChR). Finally, ACh is hydrolyzed by acetylcholinesterase (AChE) to choline and acetate. In turn, the derived- choline (at least 50% into neurons) is recovered by high-affinity choline transporter (CHT) that supports a continuous production and release of ACh [3, 4]. Moreover, a butyrylcholinesterase (BuChE), also known as pseudocholinesterase, or nonspecific cholinesterase, catalyses the hydrolysis of choline esters [5]. Choline, itself, binds to nAChR [6]. ACh, ChAT, VAChT, nAChR, mAChR, AChE and CHT are all components of the cholinergic system. In a single non-neuronal cell both nAChR and mAChR are utilized for communication between cells, for maintaining their phenotypic functions and consequently for organ homoeostasis [1, 2].