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Exogenous norepinephrine attenuates the efficacy of sunitinib in a mouse cancer model
Guo-Hua Deng, Jie Liu, Jie Zhang
1Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan Province 610041, China. jiangyu1973@hotmail.com.
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 β-AR/cAMP/PKA (β-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 β-AR/cAMP/PKA signaling pathway and could be inhibited by propranolol, a β-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.
Insights
Norepinephrine (NE), a stress hormone, reduces sunitinib efficacy in solid tumors. Combining sunitinib with propranolol may improve cancer treatment outcomes in patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Sunitinib shows variable efficacy in solid tumors, differing between preclinical models and clinical settings.
- Chronic stress in cancer patients involves hormones like norepinephrine (NE), potentially explaining efficacy disparities.
- Investigating NE's role in sunitinib response is crucial for understanding clinical outcomes.
Purpose of the Study:
- To determine if norepinephrine (NE) influences the efficacy of sunitinib in solid tumors.
- To elucidate the mechanisms by which NE affects sunitinib treatment.
- To explore potential combination therapies involving sunitinib and NE-blocking agents.
Main Methods:
- In vitro and in vivo studies assessed NE's effect on B16F1 melanoma cells treated with sunitinib.
- The study analyzed the β-adrenergic receptor/cyclic adenosine monophosphate/protein kinase A (β-AR/cAMP/PKA) signaling pathway in lung adenocarcinoma cells.
- Propranolol, a beta-blocker, was used to investigate pathway inhibition.
Main Results:
- Norepinephrine increased VEGF, IL-8, and IL-6 expression in vitro.
- NE stimulated tumor growth in vivo, mediated by the β-AR/cAMP/PKA pathway.
- Tumor growth stimulation by NE was inhibited by propranolol.
Conclusions:
- Exogenous norepinephrine significantly attenuates the efficacy of sunitinib in solid tumors.
- Combining sunitinib with propranolol presents a potential novel therapeutic strategy for solid tumors.
- Targeting stress pathways may enhance sunitinib's effectiveness in clinical cancer treatment.
