Activation by stress on sympathetic nervous system results in the

Activation by stress on sympathetic nervous system results in the release of catecholamines from the adrenal selleckchem medulla and sympathetic nerve terminals [6, 10]. Catecholamines consist of several kinds of substances such as dopamine, histamine, serotonin, epinephrine and norepinephrine (NE). The last one is regarded as the most potential SRH related to tumors in mammals [10, 11]. As ligands, catecholamines can bind adrenergic receptors (ARs) coupled with G-protein which can be classified as several subtypes such as α1, α2, β1, β2 and β3 ARs. Many types of ARs locate on tumor cells, providing the theory that chronic stress impacts on the progression of cancer.

Furthermore, the effect of stress could be mimicked with NE or β2-AR agonists, and abolished with surgical sympathetic denervation, β-AR antagonists MK-8931 datasheet or knocking down β2-AR gene by small interfering RNA [6, 10, 12]. It is accepted that a solid tumor can not progress HDAC inhibitor without angiogenesis. VEGF, one of

the most important angiogenic factors, can recruit and induce endothelial cells to proliferate and migrate, thereby starting the critical step of tumor expansion. Previous studies have demonstrated that NE upregulates VEGF, IL-8, IL-6 and MMP expression levels in some kinds of tumor cells in vitro such as melanoma, breast cancer, colon cancer, prostate cancer, ovary cancer, pancreatic cancer and nasopharynx cancer. Besides, migration of cancer cells can be stimulated by NE, which can be blocked by nonselective β-AR antagonist, propranolol [7–9, 13–18]. In mouse models in vivo, chronic stress

stimulates the growth, progression and metastasis of tumors, which can also be inhibited by propranolol [13–15, 19]. The clinical research reported that propranolol lowered the rate of breast cancer-specific mortality, cancer recurrence and distant metastasis, thus improved relapse-free survival and cancer specific survival [20–22]. Tumor angiogenesis plays a key role in development of solid tumors. Sunitinib, one kind of BCKDHA anti-angiogenic drugs, is a tyrosine kinase inhibitor with the ability of blocking VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, c-Kit and RET. It can induce tumor cell death and inhibit tumor proliferation and vascularization [23–25]. However, in clinic, treatment with sunitinib alone is of poor curative effect or even inefficacious for many types of solid tumors. On the contrary, sunitinib exhibits satisfactory efficacy in mouse homografts of melanoma, Lewis lung cancer, renal cancer and colon cancer, and xenografts of human colorectal cancer in vivo[24, 26–28]. Additionally, monotherapy with anti-angiogenic drugs including endostatin and bevacizumab also shows the discrepancy between clinical and preclinical results [29, 30].

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