Improving the Propranolol Treatment of Melanoma—Reply

In Reply We are grateful to Dr Patanè for his comments and suggestions about issues that give us the opportunity to consider additional properties of propranolol that may be of importance to interpret our results. Propranolol is an archetypical drug in terms of both pharmacokinetic and pharmacodynamic complexity. Together with polymorphisms of metabolic enzymes, additional factors, such as age, smoking, xenobiotics, and food, modulate plasma concentrations, contributing to variable pharmacokinetic profiles in different individuals. The recently reported U-shaped dose-response curve for the inhibition of melanoma growth supports the dose dependency of propranolol effects. On the other hand, it is well known that similar propranolol concentrations exert multifaceted pharmacological effects. In addition to unselective agonism of β₁- and β₂-adrenergic receptors, propranolol acts as an inverse agonist or partial agonist, with an unexpected G protein- and β-arrestin–independent mechanism, and it is also likely to target the β₃-adrenergic receptor, which increasing evidence supports as a player in melanoma growth. Finally, evidence is accumulating about immunological mechanisms that may mediate synergistic effects of propranolol and immunotherapy.

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