Will β-Blockers Live up to the Maxim of Sir James Black, Their Creator?

b-Blockers are widely prescribed. However, there has been a decline in their use for the treatment of hypertension as they have been implicated in raising triglycerides, lowering highdensity lipoprotein cholesterol, inducing glucose intolerance, and possibly unmasking diabetes. Additionally, antihypertensive drugs mediating their effect through the renin–angiotensin–aldosterone system as well as calcium channel blockers have been shown to reduce the risk of diabetes; as a consequence, these drugs are preferably prescribed over b-blockers. However, the results of a recent pilot study may reinvigorate this lost interest. Although certain antihypertensive drugs such as angiotensin II (Ang II) receptor blockers and angiotensinconverting enzyme inhibitors have been implicated in increasing cancer risk, epidemiological studies substantiate that b-blocker treatment has no effect in causing or promoting cancer growth. The study by Powe et al, which was conducted on a small number of patients with breast cancer, suggested that b-blockers restricted metastases, cancer recurrence, and cancer-specific mortality. These encouraging results prompted us to review the literature to identify a plausible mechanism by which b-blockers may mediate anticancer effects. The antihypertensive effect of b-blockers is mediated predominantly by antagonizing the stimulation of b1and b2-adrenoceptors (ARs) by catecholamines. b-Adrenoceptor agonists bind to b1-AR present predominantly in the heart and renal juxtaglomerular apparatus (JGA). Stimulation of b1-AR in the JGA leads to the increased secretion of renin, concomitantly leading to the production of Ang II (activation of the renin– angiotensin–aldosterone system [RAS]; Figure 1). Molecular and in vivo studies have indicated that Ang II via its Ang II type 1 (AT1) and type 2 (AT2) receptors influence malignancy. 10 Angiotensin II-AT1 interaction promotes tumor growth, metastasis, and angiogenesis by the increased production of growth factors as well as by the induction of expression of proto-oncogenes (Figure 1). Angiotensin II-AT2 interaction in a cyclic guanosine monophosphate (cGMP)-dependant manner leads to the phosphorylation of vasodilator stimulated phosphoprotein (VASP) resulting in the reorganization of actin cytoskeleton and enhancement of angiogenesis (Figure 1). With regard to b2-AR, their density has been found to be high in cancer cells in prostate carcinoma. The mechanistic foundation behind this association can be explained by the modulating effects of b2-AR stimulation on the p38 mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt pathways (Figure 1; pathways involved in the control of cell cycle and apoptosis). Indeed, studies in mice reveal that stress-induced neuroendocrine activation leads to a 30-fold increase in metastasis mediated by b2-AR, the effects of which can be inhibited by propranolol (a nonselective b-blocker). Blocking the stimulation of both b1 and b2-AR will inhibit the above-mentioned cellular processes, in turn could reduce metastases. More animal experiments and clinical trials with cancer as the outcome need to be performed before b-blockers can supplement existing cancer therapies. b-Blockers may confirm the maxim Sir James Black ‘‘that the most fruitful basis of the discovery of a new drug is to start with an old drug. ’’ In the meantime, clinicians should be aware of the plausible positive association we describe above.