A NEWLY SYNTHESIZED MOLECULE DERIVED FROM RUTHENIUM CATION, WITH ANTITUMOR-ACTIVITY, ACTIVATES NADPH OXIDASE IN HUMAN NEUTROPHILS

To determine the nature of the mechanism by which certain derived ruth enium (Ru) complexes induce regression in tumour growth, we have inves tigated the possibility that this mechanism was associated with an inc rease of superoxide anion (O-2(-.)) production by phagocytic cells, wh ich are usually found in tumour nodes. Here we present evidence that a newly synthesized complex, Ru3+-propylene-1,2-diaminotetra-acetic aci d (Ru-PDTA), derived from Ru and the sequestering ligand (PDTA), speci fically stimulates O-2(-.) production. This increase was associated wi th the translocation of cytosolic factors p47(phox) and p67(phox) of N ADPH oxidase to the plasma membrane. The Ru-PDTA-complex-dependent O-2 (-.) production was abrogated by staurosporine, partially inhibited by diphenylene iodonium, and it was insensitive to pertussis toxin or di butyryl cyclic AMP pretreatment. An increase of cytosolic Ca2+ levels were also detected in neutrophils treated with the Ru-PDTA complex. Al so, Ru-PDTA complex induced the phosphorylation of tyrosine residues o f several proteins as assessed by Western blotting. Present data are c onsistent with the possibility that Ru-PDTA-dependent antitumour effec ts are due in part to the complex's ability to stimulate the release o f toxic oxygen metabolites from phagocytic cells infiltrating tumour m asses.