Marisa Coelho1,2,3, Cátia Soares-Silva1,2, Daniela Brandão1,4, Franca Marino3, Marco Cosentino3, Laura Ribeiro5,6,7. 1. Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal. 2. I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. 3. Center for Research in Medical Pharmacology, University of Insubria, Varese, Italy. 4. Department of Medical Education and Simulation, Faculty of Medicine, University of Porto, Porto, Portugal. 5. Department of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal. lribeiro@med.up.pt. 6. I3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. lribeiro@med.up.pt. 7. Department of Medical Education and Simulation, Faculty of Medicine, University of Porto, Porto, Portugal. lribeiro@med.up.pt.
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.
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.
Authors: José López-Sendón; Karl Swedberg; John McMurray; Juan Tamargo; Aldo P Maggioni; Henry Dargie; Michal Tendera; Finn Waagstein; Jan Kjekshus; Philippe Lechat; Christian Torp-Pedersen Journal: Eur Heart J Date: 2004-08 Impact factor: 29.983
Authors: Helen P S Wong; Judy W C Ho; Marcel W L Koo; Le Yu; William K K Wu; Emily K Y Lam; Emily K K Tai; Joshua K S Ko; Vivian Y Shin; Kent Man Chu; Chi Hin Cho Journal: Life Sci Date: 2011-04-30 Impact factor: 5.037
Authors: M Cosentino; R Bombelli; M Ferrari; F Marino; E Rasini; G J Maestroni; A Conti; M Boveri; S Lecchini; G Frigo Journal: Life Sci Date: 2000-12-08 Impact factor: 5.037
Authors: Susan K Lutgendorf; Steven Cole; Erin Costanzo; Sarah Bradley; Jeremy Coffin; Sarvenaz Jabbari; Kaitlin Rainwater; Justine M Ritchie; Maria Yang; Anil K Sood Journal: Clin Cancer Res Date: 2003-10-01 Impact factor: 12.531
Authors: Xuan Liu; William K K Wu; Le Yu; Zhi J Li; Joseph J Y Sung; Shu T Zhang; Chi H Cho Journal: J Pharmacol Exp Ther Date: 2008-03-27 Impact factor: 4.030
Authors: Mounia Azzi; Pascale G Charest; Stéphane Angers; Guy Rousseau; Trudy Kohout; Michel Bouvier; Graciela Piñeyro Journal: Proc Natl Acad Sci U S A Date: 2003-09-17 Impact factor: 11.205
Authors: Jacques Ferlay; Isabelle Soerjomataram; Rajesh Dikshit; Sultan Eser; Colin Mathers; Marise Rebelo; Donald Maxwell Parkin; David Forman; Freddie Bray Journal: Int J Cancer Date: 2014-10-09 Impact factor: 7.396
Authors: Muhammad Bilal Ahmed; Abdullah A A Alghamdi; Salman Ul Islam; Joon-Seok Lee; Young-Sup Lee Journal: Cells Date: 2022-06-24 Impact factor: 7.666
Authors: Corina Behrenbruch; Carolyn Shembrey; Sophie Paquet-Fifield; Christina Mølck; Hyun-Jung Cho; Michael Michael; Benjamin N J Thomson; Alexander G Heriot; Frédéric Hollande Journal: Clin Exp Metastasis Date: 2018-01-15 Impact factor: 4.510