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.