A newly synthesized molecule derived from ruthenium cation, with antitumour activity, activates NADPH oxidase in human neutrophils.
To determine the nature of the mechanism by which certain derived ruthenium (Ru) complexes induce regression in tumour growth, we have investigated the possibility that this mechanism was associated with an increase of superoxide anion (O2-. production by phagocytic cells, which are usually found in tumour nodes. Here we present evidence that a newly synthesized complex, Ru3+-propylene-1, 2-diaminotetra-acetic acid (Ru-PDTA), derived from Ru and the sequestering ligand (PDTA), specifically stimulates O2-. production. This increase was associated with the translocation of cytosolic factors p47(phox) and p67(phox) of NADPH oxidase to the plasma membrane. The Ru-PDTA-complex-dependent O2-. production was abrogated by staurosporine, partially inhibited by diphenylene iodonium, and it was insensitive to pertussis toxin or dibutyryl cyclic AMP pretreatment. An increase of cytosolic Ca2+ levels were also detected in neutrophils treated with the Ru-PDTA complex. Also, Ru-PDTA complex induced the phosphorylation of tyrosine residues of several proteins as assessed by Western blotting. Present data are consistent with the possibility that Ru-PDTA-dependent antitumour effects are due in part to the complex's ability to stimulate the release of toxic oxygen metabolites from phagocytic cells infiltrating tumour masses.
Carballo
M
M
Departamento de Bioquimica M-edica y Biologia Molecular, Facultad de Medicina, Universidad de Sevilla, Av. Sánchez Pizjuan 4, Sevilla-41009, Spain.
Vilaplana
R
R
Márquez
G
G
Conde
M
M
Bedoya
F J
FJ
González-Vílchez
F
F
Sobrino
F
F
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002412:Cations; D002451:Cell Compartmentation; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D017136:Ion Transport; D019255:NADPH Oxidases / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects*; D014443:Tyrosine / Q000378:metabolism
D000970:Antineoplastic Agents; D002412:Cations; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C109683:propylene-1,2-diaminotetraacetic acid-ruthenium(III) complex; D014443:Tyrosine; D004492:Edetic Acid; D019255:NADPH Oxidases; D002118:Calcium