Title:Cholinergic Receptors as Target for Cancer Therapy in a Systems Medicine Perspective
Volume: 14
Issue: 9
Author(s): P. Russo, A. Del Bufalo, M. Milic, G. Salinaro, M. Fini and A. Cesario
Affiliation:
Keywords:
ACh, complex disease, drug discovery and development, mAChR, nAChR, systems biology, systems
medicine, therapy.
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-proteincoupled
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 druginhibition
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.
