Cholinergic receptors as target for cancer therapy in a systems medicine perspective

P. Russo, A. Del Bufalo, M. Milic, G. Salinaro, M. Fini, A. Cesario

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1126-1138
Number of pages13
JournalCurrent Molecular Medicine
Volume14
Issue number9
Publication statusPublished - Jan 1 2014

Fingerprint

Cholinergic Receptors
Systems Analysis
Medicine
Cells
Acetylcholine
Neoplasms
Colonic Neoplasms
Cholinergic Agents
Therapeutics
Lung Neoplasms
Cell proliferation
Nicotinic Receptors
Cell growth
Polyphenols
Epithelial Cells
Muscarinic Receptors
Breast Neoplasms
GTP-Binding Proteins
Neurons
Cholinergic Neurons

Keywords

  • ACh
  • Complex disease
  • Drug discovery and development
  • mAChR
  • nAChR
  • Systems biology
  • Systems medicine
  • Therapy

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Medicine(all)

Cite this

Cholinergic receptors as target for cancer therapy in a systems medicine perspective. / Russo, P.; Del Bufalo, A.; Milic, M.; Salinaro, G.; Fini, M.; Cesario, A.

In: Current Molecular Medicine, Vol. 14, No. 9, 01.01.2014, p. 1126-1138.

Research output: Contribution to journalArticle

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