Roxithromycin inhibits constitutive activation of nuclear factor {kappa}B by diminishing oxidative stress in a rat model of hepatocellular carcinoma.
OBJECTIVE
Recently, 14-member macrolide antibiotics such as clarithromycin and roxithromycin have been shown to have anticancer and antiangiogenic effects. We investigated the suppressive effect of roxithromycin on accelerated hepatocellular carcinoma growth in a rat hepatocarcinogenetic model and compared results with effects from TNP-470.


METHODS
Tumor was induced by oral diethylnitrosamine administration for 17 weeks. Normal saline, TNP-470 (50 mg/kg), or roxithromycin (40 or 100 mg/kg) was administered i.p. thrice per week from week 10 to 17.


RESULTS
Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Tumor growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of nuclear factor kappaB, and increased lipid peroxidation level. All these effects were absent in animals that received roxithromycin or TNP-470. The inhibitory effect of roxithromycin was dose dependent and no clear differences were noted between groups given roxithromycin 100 mg/kg and TNP-470 50 mg/kg.


CONCLUSIONS
Our results indicate that roxithromycin inhibits oxidative stress, nitric oxide production, and nuclear factor kappaB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.
Ueno
Shinichi
S
Department of Surgical Oncology and Digestive Surgery, School of Medicine, Kagoshima University, Kagoshima, Japan. ueno1@m.kufm.kagoshima-u.ac.jp
Aoki
Dai
D
Kubo
Fumitake
F
Hiwatashi
Kiyokazu
K
Matsushita
Kenji
K
Oyama
Tohru
T
Maruyama
Ikuro
I
Aikou
Takashi
T
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D003510:Cyclohexanes; D004052:Diethylnitrosamine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D018384:Oxidative Stress; D010920:Placenta / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D015575:Roxithromycin / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D002273:Carcinogens; D003510:Cyclohexanes; D016328:NF-kappa B; D012717:Sesquiterpenes; D015575:Roxithromycin; D004052:Diethylnitrosamine; D019001:Nitric Oxide Synthase; D005982:Glutathione Transferase; D000077609:O-(Chloroacetylcarbamoyl)fumagillol