Recent studies sight b-adrenergic receptor (AR) antagonists as novel therapeutic agents for melanoma, as they may reduce disease progression. Here within, we evaluated the expression of b-ARs in a series of human cutaneous melanocytic lesions, and studied the effect of their endogenous agonists, norepinephrine (NE) and epinephrine (E), on primary and metastatic human melanoma cell lines. Using immunohistochemistry, we found that both b1-and b2-ARs are expressed in tissues from benign melanocytic naevi, atypical naevi and malignant melanomas and that expression was significantly higher in malignant tumours. Melanoma cell lines (human A375 primary melanoma cell line and human Hs29-4T metastatic melanoma cell lines) also expressed b1-and b2-ARs by measuring transcripts and proteins. NE or E increased metalloprotease-dependent motility, released interleukin-6 and 8 (IL-6, IL-8) and vascular endothelial growth factor (VEGF). These effects of catecholamines were inhibited by the unselective b-AR antagonist propranolol. The role of soluble factors elicited by catecholamines seemed pleiotropic as VEGF synergized with NE increased melanoma invasiveness through 3D barriers, while IL-6 participated in stromal fibroblast activation towards a myofibroblastic phenotype. Our results indicate that NE and E produce in vitro via b-ARs activation a number of biological responses that may exert a pro-tumorigenic effect in melanoma cell lines. The observation that b-ARs are upregulated in malignant melanoma tissues support the hypothesis that circulating catecholamines NE and E, by activating their receptors, favour melanoma progression in vivo. Melanoma represents the most aggressive type of skin cancer, with an increasing incidence found especially in young adults. A significant reduction in mortality has been not observed, despite a noteworthy improvement in early diagnosis achieved in recent years. 1 At present, no medical option can cure metastatic melanoma (MM) and the only effective treatment for the eradication of the disease is early-phase surgery. 2 Hence, increased knowledge of the biological pathways underlying the process of melanoma dissemination and metastasis is crucial in order to identify new therapeutic targets.Previous studies have shown that various human solid tumours, such as breast, colon, prostatic, ovary, nasopharyngeal and oral cancer, express b2-adrenoceptor (b2-AR), raising the possibility that such receptors may affect invasion and dissemination processes. [3][4][5][6][7][8] Moreover, some stress neurotransmitters, such as norepinephrine (NE) and epinephrine (E), have been demonstrated to contribute to the regulation of tumour cell invasion, at least in part through b-AR activation. 6,7,9 Interactions between tumour cells and soluble factors originated from the nervous system has recently been proposed to favour metastasis formation. 10 Improved survival rates have been demonstrated in mice with metastatic tumour by combined administration of b-AR antagonists. 11 In addition, recent evidence suggests a ...

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Immunotoxins are chimeric proteins consisting of a toxin coupled to an antibody. To date, several clinical trials have been conducted, and some are still ongoing, to evaluate their anti-tumor efficacy. In this view, we chemically constructed an anti-CD20 immunotoxin with the mAb Rituximab and the type 1 ribosome-inactivating protein (RIP) saporin-S6, designed for B cells non-Hodgkin's lymphoma (NHL) therapy. This immunotoxin showed a specific cytotoxicity for the CD20 þ cell lines Raji and D430B, evidenced by inhibition of protein synthesis, evaluation of apoptosis and clonogenic assay. Upon conjugation, saporin-S6 increased its toxicity on target cells by at least 2 logs, with IC 50 values of 0.1-0.3 nM. The percentage of AnnexinV þ cells was over 95% in both cell lines treated with 10 nM immunotoxin. A complete elimination of Raji clones was reached with the 10 nM immunotoxin, whereas a mixture of free RIP and mAb gave about 90% of clonogenic growth. Rituximab/ saporin-S6, at 10 nM concentration, also induced apoptosis in 80% of lymphoma cells from NHL patients. Moreover, sensitivity of Raji to Rituximab/saporin-S6 was augmented when cells were coincubated with Fludarabine. The synergistic toxic effect of the two drugs led to a total elimination of the neoplastic population.

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