5-Fluorouracil inhibits nitric oxide production through the inactivation of IkappaB kinase in stomach cancer cells.
The antimetabolite 5-fluorouracil (5-FU) is one of the more prominent clinical antitumor agents available for the treatment of stomach and colorectal cancers. In the present study, we characterized the effects of 5-FU on nitric oxide (NO) production by cells from the stomach cancer cell line NCI-N87. A cytokine mixture [interleukin (IL)-1beta/interferon (IFN)-gamma] increased the production of NO by stomach cancer cells in a concentration- and time-dependent manner. Pretreatment with 5-FU inhibited the production of NO that was stimulated by the cytokine mixture and reduced the expression of iNOS. The cytokine mixture activated nuclear factor kappaB (NF-kappaB) in a concentration- and time-dependent manner, which was blocked by 5-FU pretreatment. The pretreatment with 5-FU stabilized IkappaBalpha and inactivated IkappaB kinase. Collectively, these data suggest that the efficacy of 5-FU may include the inactivation of IkappaB kinase and the inhibition of NO production.
Jung
In Duk
ID
College of Medicine, Konyang University, Nonsan 320-711, South Korea.
Yang
So Young
SY
Park
Chang Gyo
CG
Lee
Kyung Bok
KB
Kim
Jong Seung
JS
Lee
Seok Yong
SY
Han
Jeung Whan
JW
Lee
Hyang Woo
HW
Lee
Hoi Young
HY
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D005472:Fluorouracil