Weekly inhaled salmeterol xinafoate, a selective β2 adrenergic receptor agonist drug, therapeutically inhibits cancer growth and prolongs survival in vivo

Humans have spent approximately 99.5% of the 2.5 million years of evolutionary history as hunter-gatherers, which helped to evolutionarily mold our minds and bodies to the hunting and gathering lifestyle. Physical activity associated with hunting animals, gathering plants, and evading predators is essential for human survival, evolution, and prosperity. Thus, physical activity (acute stress) is mostly beneficial to the body, whereas psycho-emotional stress (chronic stress) is usually detrimental at the psychological, physiological, and pathological levels. Although physical activity exerts anticancer effects and psycho-emotional stress exhibits cancer-promoting effects, both function through the same pathway involving activation of the sympathetic nervous system, release of catecholamines, and stimulation of {beta}2 adrenergic receptor ({beta}2AR) expressed on cancer cells. Here, salmeterol xinafoate was chosen to mimic physical activity. A once-weekly administration of salmeterol xinafoate by the intraperitoneal, inhalation, or transdermal route, dose-dependently extended latency, reduced cancer incidence and growth, and prolonged survival in vivo. Remarkably, the best complete response rates were 75%, 30%, and 71.43% for the therapeutic treatment of lung cancer, breast cancer, and melanoma, respectively. Notably, the salmeterol xinafoate doses used in our experiments are comparable to those used in patients. Moreover, in endogenous {beta}2AR knockout cancer cells, the exogenous {beta}2AR mutant with impaired salmeterol xinafoate binding or downstream signaling prevented the anticancer effects of salmeterol xinafoate in vivo, demonstrating the on-target action of salmeterol xinafoate on cancer cells and the requirement of the downstream signaling pathway. Finally, we showed that treatment with salmeterol xinafoate dose-dependently decreased the self-renewal capacity of lung cancer stem cells, breast cancer stem cells, and melanoma stem cells. From the perspective of human evolution into cancer biology, our study reveals that {beta}2AR represents an ideal anticancer drug target and that salmeterol xinafoate monotherapy has strong anticancer activity.