Silver(I)/6-hydroxyiminolumazine compounds differently modify renin–angiotensin system-regulating aminopeptidases A and N in human neuroblastoma and glioma cells

Abstract

We have described that local tissue renin–angiotensin-system (RAS) is involved in tumor growth in a rat model of experimental glioma in vivo, through the modification of their corresponding local proteolytic regulatory enzymes. Thus, we have found a time-dependent significant decrease in aminopeptidase N (APN) and a significant increase in aminopeptidase A (APA) activities concomitantly with tumor growth in tumor tissue whereas no changes were found in circulating aminopeptidase activities; we suggested that angiotensin peptides may play an essential step in both tumor infiltration and associated angiogenesis. Here we analyze in vitro the antiproliferative efficacy, apoptotic properties and effects of three new disilver complexes containing E-6-(hydroxyimino)ethyl-1,3,7-trimethyllumazine (lumazine=pteridine-2,4(1H,3H)-dione) on RAS-regulating APA and APN specific activities in human neuroblastoma and glioma cell lines NB69 and U373-MG. Disilver compounds showed cytotoxicity against both cell lines, although their potency was different for each cell type. Furthermore, NB69 cells need higher concentrations of silver complexes than U373-MG cells to obtain a 50% growth inhibition. All compounds showed apoptotic effects, with U373-MG cells being more susceptible. The three silver complexes tested also show a dose-dependent inhibitory effect on APA activity in NB69 and U373-MG cells, although U373-MG cells are more sensitive. On the contrary, none of them showed effects on APN activity in NB69 neuroblastoma cells whereas the three compounds showed a dose-dependent stimulatory effect on APN activity in U373-MG glioma cells with a similar potency. Disilver complexes show specific antitumor activity against brain tumor cells acting through the paracrine regulating system mediated by local tissue RAS.