5-Aza-2'-deoxycytidine and paclitaxel inhibit inducible nitric oxide synthase activation in fibrosarcoma cells.
Given the important role of gaseous free radical nitric oxide (NO) in tumor cell biology, we investigated the ability of the anti-cancer drugs 5-Aza-2'-deoxycytidine (ADC) and paclitaxel to modulate NO production in mouse L929 fibrosarcoma cells. Both drugs reduced IFN-gamma-stimulated NO release in cultures of L929 and primary fibroblasts, but not in mouse peritoneal macrophages. The inhibitory effect was due to the reduced expression of inducible NO synthase (iNOS), the enzyme responsible for cytokine-induced intracellular NO synthesis, as both agents markedly suppressed the interferon-gamma (IFN-gamma)-triggered increase in iNOS concentration in L929 cells. In addition, ADC and paclitaxel prevented the IFN-gamma-triggered activation of p44/p42 mitogen-activated protein (MAP) kinase in L929 fibroblasts, suggesting a possible mechanism for the observed inhibition of iNOS expression. These results might have important implications for the therapeutic effect of ADC and paclitaxel, since their inhibitory action on NO release partly neutralized the NO-dependent toxicity of IFN-gamma on L929 fibrosarcoma cells.
Miljkovic
Djordje
D
Laboratory of Immunology, Institute for Biological Research Sinisa Stankovic, 29. Novembra 142, 11060 Belgrade, Serbia. georgije_zw@yahoo.com
Cvetkovic
Ivana
I
Sajic
Marija
M
Vuckovic
Olivera
O
Harhaji
Ljubica
L
Markovic
Milos
M
Trajkovic
Vladimir
V
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005354:Fibrosarcoma / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D000077209:Decitabine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001374:Azacitidine; D017239:Paclitaxel