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.
- Azzi M, Charest PG, Angers S, Rousseau G, Kohout T, Bouvier M, Pineyro G (2003) Β-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc Natl Acad Sci USA 100:11406–11411. doi: 10.1073/pnas.1936664100 CrossRefPubMedPubMedCentralGoogle Scholar
- Eng JW, Kokolus KM, Reed CB, Hylander BL, Ma WW, Repasky EA (2014) A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol Immunother 63:1115–1128. doi: 10.1007/s00262-014-1617-9 CrossRefPubMedPubMedCentralGoogle Scholar
- Heitz F et al (2013) Impact of β blocker medication in patients with platinum sensitive recurrent ovarian cancer-a combined analysis of 2 prospective multicenter trials by the AGO study group NCIC-CTG and EORTC-GCG. Gynecol Oncol 129:463–466. doi: 10.1016/j.ygyno.2013.03.007 CrossRefPubMedGoogle Scholar
- López-Sendón J, Swedberg K, McMurray J, Tamargo J, Maggioni AP, Dargie H, Tendera M, Waagstein F, Kjekshus J, Lechat P, Torp-Pedersen C (2004) Expert consensus document on angiotensin converting enzyme inhibitors in cardiovascular disease. The task force on ACE-inhibitors of the European Society of Cardiology. Eur Heart J 25:1454–1470. doi: 10.1016/j.ehj.2004.06.003
- Lutgendorf SK et al (2003) Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Cancer Res 9:4514–4521Google Scholar
- Perez D, Hébert T, Cotecchia S, Doze VA, Graham RM, Bylund DB, Altosaar K, Devost D, Gora S, Goupil E, Kan S, Machkalyan G, Michel MC, Sleno R, Summers R, Zylbergold P, Balaji P, Bond RA, Eikenburg DC, Hieble JP, Minneman KP, Sergio P, Hills R (2016) Adrenoceptors, introduction. Last modified on 10/08/2015. IUPHAR/BPS Guide Pharmacol. http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=4. Accessed 30 May 2016
- Pimentel MA, Chai MG, Le CP, Cole SW, Sloan EK (2012) Sympathetic nervous system regulation of metastasis. In: Rahul Jandial and Kent Hunter (eds) Metastatic cancer: integrated organ system and biological approach, pp 1–11Google Scholar
- Rangarajan S, Enserink JM, Kuiperij HB, de Rooij J, Price LS, Schwede F, Bos JL (2003) Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the β 2-adrenergic receptor. J Cell Biol 160:487–493. doi: 10.1083/jcb.200209105 CrossRefPubMedPubMedCentralGoogle Scholar
- Schuller HM, Tithof PK, Williams M, Plummer H 3rd (1999) The tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is a β-adrenergic agonist and stimulates DNA synthesis in lung adenocarcinoma via β-adrenergic receptor-mediated release of arachidonic acid. Cancer Res 59:4510–4515PubMedGoogle Scholar
- Westfall TCWaDP (2011) Adrenergic agonists and antagonists. In: Brunton LL (ed) Goodman & Gilman’s the pharmacological basis of therapeutics, 12th edn. The McGraw-HillGoogle Scholar