Exogenous norepinephrine attenuates the efficacy of sunitinib in a mouse cancer model

Background: Sunitinib alone exhibits satisfactory efficacy in several mouse homografts and xenografts but unsatisfactory efficacy in many kinds of solid tumors in clinic. Different from animals, receiving a diagnosis of cancer impacts chronic stress on patients. Here, we examine whether norepinephrine (NE), one of the most potent stress related hormones, leads to the difference in the efficacy of sunitinib between clinical and preclinical trials. Methods: The influence of NE on mouse melanoma B16F1 cells under sunitinib was evaluated in vitro and in vivo. The beta-AR/cAMP/PKA (beta-adrenoceptor/cyclic adenosine monophosphate/protein kinase A) signaling pathway was also evaluated in human lung adenocarcinoma cells. Results: We found that NE upregulated the expression of VEGF, IL-8 and IL-6 in vitro and stimulated tumor growth in vivo, which was mediated by beta-AR/cAMP/PKA signaling pathway and could be inhibited by propranolol, a beta-blocker for hypertension for decades. Conclusions: This research indicates exogenous norepinephrine attenuates the efficacy of sunitinib, and a combination of sunitinib and propranolol might be suggested as a new strategy in solid tumor in clinic.