title: β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal.|I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Coelho
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal.|I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Cátia
authors.initials: C
authors.lastname: Soares-Silva
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal.|Department of Medical Education and Simulation, Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Daniela
authors.initials: D
authors.lastname: Brandão
authors.affiliation: Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Marino
authors.affiliation: Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Cosentino
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal. lribeiro@med.up.pt.|I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. lribeiro@med.up.pt.|Department of Medical Education and Simulation, Faculty of Medicine, University of Porto, Porto, Portugal. lribeiro@med.up.pt.
authors.forename: Laura
authors.initials: L
authors.lastname: Ribeiro
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002986:Clinical Trials as Topic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009638:Norepinephrine / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D000319:Adrenergic beta-Antagonists; D000970:Antineoplastic Agents; D011943:Receptors, Adrenergic, beta; D009638:Norepinephrine
keywords: Adrenergic system; Cancer; Catecholamines; Proliferation; β-Blockers