β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives
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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.
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.
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.
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.
KeywordsAdrenergic system Catecholamines Cancer Proliferation β-Blockers
Vascular endothelial growth factor
Protein kinase A
Cyclic adenosine monophosphate
Extracellular signal-regulated kinase
Nuclear factor κB
Activator protein 1
CAMP response element binding protein
Epidermal growth factor
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.
This article does not contain any studies with human participants or animals performed by any of the authors.
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