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Journal of Cancer Research and Clinical Oncology

, Volume 143, Issue 2, pp 275–291 | Cite as

β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives

  • Marisa Coelho
  • Cátia Soares-Silva
  • Daniela Brandão
  • Franca Marino
  • Marco Cosentino
  • Laura Ribeiro
Review – Clinical Oncology

Abstract

Purpose

In this review, we aimed to present and discuss the available preclinical and epidemiological evidences regarding the modulation of cancer cell proliferation by β-adrenoceptors (β-AR), with a specific focus on the putative effects of β-blockers according to their pharmacological properties.

Methods

A comprehensive review of the published literature was conducted, and the evidences concerning the involvement of β-AR in cancer as well as the possible role of β-blockers were selected and discussed.

Results

The majority of reviewed studies show that: (1) All the cancer types express both β1- and β2-AR, with the exception of neuroblastoma only seeming to express β2-AR; (2) adrenergic agonists are able to increase proliferation of several types of cancers; (3) the proliferative effect seems to be mediated by both β1- and β2-AR; (4) binding to β-AR results in a cAMP transient flux which activates two major downstream effector systems: protein kinase A and EPAC and (5) β-blockers might be putative adjuvants for cancer treatment.

Conclusions

Overall, the reviewed studies show strong evidences that β-AR activation, through several intracellular mechanisms, modulate tumor cell proliferation suggesting β-blockers can be a feasible therapeutic approach to antagonize β-adrenergic response or have a protective effect per se. This review highlight the need for intensifying the research not only on the molecular mechanisms underlying the β-adrenergic influence in cancer, but also on the implications of biased agonism of β-blockers as potential antitumor agents.

Keywords

Adrenergic system Catecholamines Cancer Proliferation β-Blockers 

Abbreviations

SAM

Sympathoadrenomedullary

AD

Adrenaline

NA

Noradrenaline

ISO

Isoprenaline

PRO

Propranolol

CAs

Catecholamines

ATE

Atenolol

ICI

ICI-118,551

MET

Metoprolol

NEB

Nebivolol

LAB

Labetalol

BUT

Butoxamine

SALB

Salbutamol

BIS

Bisoprolol

CAR

Carvedilol

TERB

Terbutraline

MMP

Matrix metalloproteinase

VEGF

Vascular endothelial growth factor

PKA

Protein kinase A

cAMP

Cyclic adenosine monophosphate

ERK

Extracellular signal-regulated kinase

NFκB

Nuclear factor κB

AP-1

Activator protein 1

CREB

CAMP response element binding protein

AA

Arachidonic acid

GPCR

G-protein-coupled receptor

EGF

Epidermal growth factor

Notes

Compliance with ethical standards

Conflict of interest

Author Marisa Coelho declares that she has no conflict of interest. Author Cátia Soares-Silva declares that she has no conflict of interest. Author Daniela Brandão declares that she has no conflict of interest. Author Franca Marino declares that she has no conflict of interest. Author Marco Cosentino declares that he has no conflict of interest. Author Laura Ribeiro declares that she has no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Marisa Coelho
    • 1
    • 2
    • 3
  • Cátia Soares-Silva
    • 1
    • 2
  • Daniela Brandão
    • 1
    • 4
  • Franca Marino
    • 3
  • Marco Cosentino
    • 3
  • Laura Ribeiro
    • 1
    • 2
    • 4
  1. 1.Department of Biochemistry, Faculty of MedicineUniversity of PortoPortoPortugal
  2. 2.I3S-Instituto de Investigação e Inovação em SaúdeUniversidade do PortoPortoPortugal
  3. 3.Center for Research in Medical PharmacologyUniversity of InsubriaVareseItaly
  4. 4.Department of Medical Education and Simulation, Faculty of MedicineUniversity of PortoPortoPortugal

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