Comparing the Molecular Pharmacological Properties of Existing β-Blockers to Determine the Theoretically Most "Ideal"...

There is increasing evidence, from cellular, animal and human epidemiological studies, linking β-blockers with reductions in cancer growth and metastasis. Propranolol is the most investigated β-blocker for cancer; although as many different off-patent β-blockers exist, there is little commercial incentive to drive comparative clinical trials. To minimize any chance of endogenous β-agonist driven cancer growth or metastasis, theoretically, the "ideal" anti-cancer β-blocker would have high affinity, no partial agonism, and long duration of action at β2-adrenoceptors (and for some cancers, additionally at β1 or β3-AR). Using CHO cells stably expressing the wildtype and polymorphic variants of the human β1 and β1-adrenoceptors, this study assessed 35 β-blockers for the affinity and duration of binding (using ³H-CGP12177 whole cell binding) and intrinsic efficacy (CRE-gene transcription). Despite high affinity, some β-blockers had a short binding duration (e.g., alprenolol, bupranolol, levobunolol, nadolol and oxprenolol). Other compounds had substantial partial agonism (e.g., cyanopindolol, bucindolol, pindolol, pronethalol and xamoterol) and other compounds had a biphasic washout (e.g., bucindolol, timolol, carpindolol, and CGP12177) for reasons unknown. Considering all 3 factors, carazolol and ICI118551 may be more "ideal" than propranolol; however, carvedilol, with higher affinity and substantially longer duration of β2 (and β1) receptor binding than propranolol whilst maintaining low partial agonism, may be the most theoretically optimal. Furthermore, it is already widely used in cardiovascular medicine as an off-patent tablet. Thus, carvedilol may have more optimal molecular pharmacological characteristics for an "anti-cancer" β-blocker than propranolol and could enter prospective comparative clinical trials without needing any further clinical workup.