β-Adrenergic modulation of cancer cell proliferation: available evidence and clinical perspectives

In this review, we aimed to present and discuss the available preclinical and epidemiological evidences regarding the modulation of cancer cell proliferation by beta-adrenoceptors (beta-AR), with a specific focus on the putative effects of beta-blockers according to their pharmacological properties. A comprehensive review of the published literature was conducted, and the evidences concerning the involvement of beta-AR in cancer as well as the possible role of beta-blockers were selected and discussed. The majority of reviewed studies show that: (1) All the cancer types express both beta 1- and beta 2-AR, with the exception of neuroblastoma only seeming to express beta 2-AR; (2) adrenergic agonists are able to increase proliferation of several types of cancers; (3) the proliferative effect seems to be mediated by both beta 1- and beta 2-AR; (4) binding to beta-AR results in a cAMP transient flux which activates two major downstream effector systems: protein kinase A and EPAC and (5) beta-blockers might be putative adjuvants for cancer treatment. Overall, the reviewed studies show strong evidences that beta-AR activation, through several intracellular mechanisms, modulate tumor cell proliferation suggesting beta-blockers can be a feasible therapeutic approach to antagonize beta-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 beta-adrenergic influence in cancer, but also on the implications of biased agonism of beta-blockers as potential antitumor agents.