Apoptosis inhibitory effect of the isothiourea compound, tri-(2-thioureido-S-ethyl)-amine.
Sulfhydril compounds, some of them with immunomodulatory activity have also been shown to modulate the induction of apoptosis. This study was performed to assess the possible apoptosis inhibitory effect of the immunomodulatory compound tri-(2-thioureido-S-ethyl)-amine (K-1) in U-937 and HL-60 leukaemia cell lines as model systems. Treatment of U-937 and HL-60 cells with K-1 inhibited etoposide (ETO)-induced apoptosis in both cell lines in a dose-dependent manner, IC(50)=200 microg/ml. The results indicate that inhibition of ETO-induced apoptosis occurs downstream of ETO-mediated cleavable complex formation but early in, or at the level of the mitochondria events of the apoptotic pathway. Further, like other isothioureas, K-1 proved to be a potent inhibitor of nitric oxide synthase. This raises the possibility that where the activation of nitric oxide synthase is involved in apoptosis induction, K-1 might also be effective. These findings suggest that K-1 may serve as a potent inhibitor of apoptosis initiated by ETO or nitric oxide.
Nagy
E
E
Central Laboratory of Immunology, Semmelweis University of Medicine, Budapest, Hungary.
Mihalik
R
R
Hrabák
A
A
Vértesi
C
C
Gergely
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D002531:Cerebellum / Q000201:enzymology; D053938:DNA Fragmentation / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D019169:Jurkat Cells / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000201:enzymology / Q000648:ultrastructure; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020298:U937 Cells / Q000187:drug effects; D019014:fas Receptor / Q000276:immunology
D000911:Antibodies, Monoclonal; D061945:Caspase Inhibitors; D019014:fas Receptor; C407427:tri-(2-thioureidoethyl)amine; D005047:Etoposide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013890:Thiourea