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Neuroblastoma (NB) is the most frequently observed among extracranial pediatric solid tumors. It displays an extreme clinical heterogeneity, in particular for the presentation at diagnosis and response to treatment, often depending on cancer cell differentiation/stemness. The frequent presence of elevated hematic and urinary levels of catecholamines in patients affected by NB suggests that the dissection of adrenergic system is crucial for a better understanding of this cancer. β3-adrenoreceptor (β3-AR) is the last identified member of adrenergic receptors, involved in different tumor conditions, such as melanoma. Multiple studies have shown that the dysregulation of the bioactive lipid sphingosine 1-phosphate (S1P) metabolism and signaling is involved in many pathological diseases including cancer. However, whether S1P is crucial for NB progression and aggressiveness is still under investigation. Here we provide experimental evidence that β3-AR is expressed in NB, both human specimens and cell lines, where it is critically involved in the activation of proliferation and the regulation between stemness/differentiation, via its functional cross-talk with sphingosine kinase 2 (SK2)/S1P receptor 2 (S1P2) axis. The specific antagonism of β3-AR by SR59230A inhibits NB growth and tumor progression, by switching from stemness to cell differentiation both in vivo and in vitro through the specific blockade of SK2/S1P2 signaling.

BACKGROUND AND PURPOSE: Stress‐related catecholamines have a role in cancer and β‐adrenoceptors; specifically, β(2)‐adrenoceptors have been identified as new targets in treating melanoma. Recently, β(3)‐adrenoceptors have shown a pleiotropic effect on melanoma micro‐environment leading to cancer progression. However, the mechanisms by which β(3)‐adrenoceptors promote this progression remain poorly understood. Catecholamines affect the immune system by modulating several factors that can alter immune cell sub‐population homeostasis. Understanding the mechanisms of cancer immune‐tolerance is one of the most intriguing challenges in modern research. This study investigates the potential role of β(3)‐adrenoceptors in immune‐tolerance regulation. EXPERIMENTAL APPROACH: A mouse model of melanoma in which syngeneic B16‐F10 cells were injected in C57BL‐6 mice was used to evaluate the effect of β‐adrenoceptor blockade on the number and activity of immune cell sub‐populations (Treg, NK, CD8, MDSC, macrophages, and neutrophils). Pharmacological and molecular approaches with β‐blockers (propranolol and SR59230A) and specific β‐adrenoceptor siRNAs targeting β(2)‐ or β(3)‐adrenoceptors were used. KEY RESULTS: Only β(3)‐, but not β(2)‐adrenoceptors, were up‐regulated under hypoxia in peripheral blood mononuclear cells and selectively expressed in immune cell sub‐populations including Treg, MDSC, and NK. SR59230A and β(3)‐adrenoceptor siRNAs increased NK and CD8 number and cytotoxicity, while they attenuated Treg and MDSC sub‐populations in the tumour mass, blood, and spleen. SR59230A and β(3)‐adrenoceptor siRNAs increased the ratio of M1/M2 macrophages and N1 granulocytes. CONCLUSIONS AND IMPLICATIONS: Our data suggest that β(3)‐adrenoceptors are involved in immune‐tolerance, which opens the way for new strategic therapies to overcome melanoma growth. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

Resveratrol (RE), a polyphenolic compound present in some food and plants, is characterized by anti-inflammatory and antioxidant properties. However, it is quickly metabolized with consequent loss of its efficacy. In this study, the antioxidant effect of 2-phenyl-benzoselenophene derivatives (VD0, VD1 and VD2) was detected in intestinal myofibroblast and osteocyte cell lines in which the oxidative stress was induced by GSH depletion or starvation, respectively. In fact, the oxidative stress is involved in pathogenesis of inflammatory bowel diseases (IBD) and in increased osteoclastogenesis in osteoporosis. Our results show that these derivatives have major antioxidant power in reducing and/or restoring radical oxygen species to control values than RE itself in both cell types. Moreover, derivatives have different antioxidant capacity in myofibroblasts and in osteocytes and this can be due to different degree of oxidative stress and structural characteristics of these compounds. Some of the synthesized RE analogs have shown anti-bacterial role in IBD and anti-resorptive activity in bone pathologies related to inflammatory and osteoporotic processes. Thus, we suggest benzoselenophene derivatives as good candidates for alternative therapy and/or therapeutic support in these pathologies.