Cytotoxic drugs regulate VEGF and IL-8 expression in human melanoma cells by A2A and A3 adenosine receptors.

Cancer patients undergoing treatment with systemic cancer chemotherapy drugs often have abnormal growth factor and cytokine profiles. Thus, serum levels of interleukin-8 (IL-8) are elevated in patients with malignant melanoma. In addition to IL-8, aggressive melanoma cells secrete, through its transcriptional regulator Hypoxia-inducible Factor 1 (HIF-1), vascular endothelial growth factor (VEGF), which promotes angiogenesis and metastasis of human cancerous cells.1,4 Whether these responses are related to adenosine, a ubiquitous mediator expressed at high concentrations in cancer and implicated in numerous inflammatory processes, is not known and is the focus of this study. We have examined whether the DNA-damaging agents etoposide (VP-16) and doxorubicin can affect IL-8, VEGF and HIF-1 expression in human melanoma cancer cells. In particular, we have investigated whether these responses are related to the modulation of the adenosine receptor subtypes, named A1, A2A, A2B and A3. We have demonstrated that A2B receptor blockade can modulate IL-8 production while blocking A3 receptors it is possible to further decrease VEGF reduction due to VP-16 and doxorubicin in melanoma cells. This understanding may present the possibility of using adenosine antagonists to reduce chemotherapy-induced inflammatory cytokine production and to improve the ability of chemotherapeutic drugs to block angiogenesis. Consequently, we conclude that adenosine receptor modulation may be useful for refining the use of chemotherapeutic drugs to treat human cancer more effectively. (1) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Simioni, C.; Leung, E.; Maclennan, S.; Baraldi, P.G.; Borea, P.A. Caffeine inhibits adenosine-induced accumulation of hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-8 expression in hypoxic human colon cancer cells. Mol Pharmacol. 2007, 72, 395-406. (2) Merighi S, Benini A, Mirandola P, Gessi S, Varani K, Leung E, Maclennan S, Baraldi, P.G.; Borea PA. Hypoxia inhibits paclitaxel-induced apoptosis through adenosine-mediated phosphorylation of bad in glioblastoma cells. Mol Pharmacol. 2007, 72, 162-72. (3) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Leung, E.; Maclennan, S.; Borea, P.A. Adenosine modulates vascular endothelial growth factor expression via hypoxia-inducible factor-1 in human glioblastoma cells. Biochem Pharmacol. 2006, 72, 19-31. (4) Merighi, S.; Benini, A.; Mirandola, P.; Gessi, S.; Varani, K.; Leung, E.; Maclennan, S.; Baraldi, P.G.; Borea, P.A. A3 adenosine receptors modulate hypoxia-inducible factor-1alpha expression in human A375 melanoma cells. Neoplasia 2005, 7, 894-903