TNP-470 inhibits oxidative stress, nitric oxide production and nuclear factor kappa B activation in a rat model of hepatocellular carcinoma.
The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-kappaB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-kappaB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-kappaB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.
Department of Physiology, University of León, 24071 León, Spain.
Jose L
JL
Mauriz
Pedro
P
Linares
Rocio I R
RI
Macias
Francisco
F
Jorquera
E
E
Honrado
Jose L
JL
Olcoz
Paquita
P
González
Javier
J
González-Gallego
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D003510:Cyclohexanes; D004052:Diethylnitrosamine / Q000494:pharmacology; D004789:Enzyme Activation; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology*; D017392:Thiobarbituric Acid Reactive Substances; D013997:Time Factors; D014841:von Willebrand Factor / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012717:Sesquiterpenes; D017392:Thiobarbituric Acid Reactive Substances; D014841:von Willebrand Factor; D004052:Diethylnitrosamine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005982:Glutathione Transferase; D005978:Glutathione; D019803:Glutathione Disulfide; D000077609:O-(Chloroacetylcarbamoyl)fumagillol