A(2B) and A(3) adenosine receptors modulate vascular endothelial growth factor and interleukin-8 expression in human melanoma cells treated with etoposide and doxorubicin.
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. 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 expressions in human melanoma cancer cells. In particular, we have investigated whether these responses are related to the modulation of the adenosine receptor subtypes, namely, A(1), A(2A), A(2B), and A(3). We have demonstrated that A(2B) receptor blockade can impair IL-8 production, whereas blocking A(3) receptors, it is possible to further decrease VEGF secretion in melanoma cells treated with VP-16 and doxorubicin. 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.
Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, 44100 Ferrara, Italy.
Stefania
S
Merighi
Carolina
C
Simioni
Stefania
S
Gessi
Katia
K
Varani
Prisco
P
Mirandola
Mojgan Aghazadeh
MA
Tabrizi
Pier Giovanni
PG
Baraldi
Pier Andrea
PA
Borea
D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005047:Etoposide / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D043682:Receptor, Adenosine A1 / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000235:genetics / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D042461:Vascular Endothelial Growth Factor A; D005047:Etoposide; D004317:Doxorubicin