Potentiation of tumor necrosis factor induced apoptosis by onconase.
Onconase (ONC) a ribonuclease from amphibian oocytes is cytostatic and cytotoxic to many human tumor lines, shows in vivo antitumor activity in mouse tumor models and is in Phase III clinical trials. The mechanism of antitumor activity of ONC is presumed to be due to its internalization, degradation of intracellular RNA and suppression of protein synthesis. Since apoptosis triggered by TNF-alpha is known to be potentiated by inhibitors of protein synthesis, we have hypothesized that it also may be potentiated by ONC. Indeed, preincubation of U-937 or HL-60 leukemic cells with 0.17 microM ONC rendered them more sensitive to induction of apoptosis by TNF-alpha or antibody to CD95 (Fas). The mechanism by which ONC amplifies the effect of TNF-alpha may involve suppression of induction of the survival genes whose expression is triggered by activation of NFkB by this factor.
Deptala
A
A
Brander Cancer Research Institute, New York Medical College, Valhalla, NY 10595, USA.
Halicka
H D
HD
Ardelt
B
B
Ardelt
W
W
Mikulski
S M
SM
Shogen
K
K
Darzynkiewicz
Z
Z
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D004357:Drug Synergism; D004527:Egg Proteins / Q000378:metabolism*; D053222:Fas Ligand Protein; D018922:HL-60 Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D012260:Ribonucleases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism
D015703:Antigens, CD; D004527:Egg Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D012260:Ribonucleases; C058703:ranpirnase