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.
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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
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Coelho, M., Soares-Silva, C., Brandão, D. et al. β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives. J Cancer Res Clin Oncol 143, 275–291 (2017). https://doi.org/10.1007/s00432-016-2278-1
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DOI: https://doi.org/10.1007/s00432-016-2278-1