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

Abstract

BackgroundSunitinib 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.MethodsThe influence of NE on mouse melanoma B16F1 cells under sunitinib was evaluated in vitro and in vivo. The β-AR/cAMP/PKA (β-adrenoceptor/cyclic adenosine monophosphate/protein kinase A) signaling pathway was also evaluated in human lung adenocarcinoma cells.ResultsWe 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 β-AR/cAMP/PKA signaling pathway and could be inhibited by propranolol, a β-blocker for hypertension for decades.ConclusionsThis 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.

Sympathetic nervous system regulation of the tumour microenvironment

“…β-adrenergic signaling can also modulate the expression of growth and survival factors —such as VEGF, IL-6, and IL-8 — that are associated with resistance to tyrosine kinase inhibitors 91,94 . Several of these studies have documented consequent impacts on tumour growth and metastasis in vivo , showing that inhibition of programmed cell death represents a bona fide mediator of SNS effects on cancer progression.…”

“…This might be particularly relevant in diseases for which current medical therapies show little efficacy (such as triple-negative breast cancer). Moreover, recent studies showing treatment-sensitizing effects of β-blockade imply some potential for value even in late-stage disease 24,52–54,62,91,94,109,121,122 .…”

Effects of trauma, hemorrhagic shock, and chronic stress on lung vascular endothelial growth factor

“…In cancer cells, VEGF expression is dependent on upon hypoxia-inducible factor (HIF)-1 induction. 18-21 HIF-1 is stimulated by norepinephrine (NE) in a dose-dependent fashion, and the non-selective beta blocker propranolol significantly inhibits NE-induced HIF-1 protein production and VEGF expression. 18-21 In our rat model, the addition of chronic stress to LCHS increased urine NE levels.…”

“…Understanding of the role of VEGF in lung tissue repair under these conditions may elucidate therapeutic strategies. Based on evidence that hypoxia and hypercatecholaminemia increase VEGF and VEGF receptor expression and function, 8, 17-21 we hypothesized that lung contusion (LC) and hemorrhagic shock (HS) would increase expression of lung VEGF and VEGF receptors, the addition of daily chronic restraint stress (CS) would exacerbate this effect, and that VEGF overexpression would be associated with pulmonary edema and impaired lung tissue healing.…”

β‐Adrenoceptors as drug targets in melanoma: novel preclinical evidence for a role of β3‐adrenoceptors

“…Among the signalling pathways involved in melanoma growth, NA acting on β 1 ‐ and β 2 ‐adrenoceptors activates the Gs/cAMP/PKA pathway thus leading to increased expression of VEGF and inflammatory cytokines (Yang et al ., ; Deng et al ., ). In addition, in human melanoma cells, propranolol has been found to inhibit the Akt and MAPK pathways thus promoting apoptosis and decreasing cell viability (Zhou et al ., ).…”