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Roxithromycin Inhibits Constitutive Activation of Nuclear Factor B by Diminishing Oxidative Stress in a Rat Model of Hepatocellular Carcinoma

Authors' Affiliations: ¹ Departments of Surgical Oncology and Digestive Surgery, ² Operative Dentistry and Endodontology, and ³ Laboratory and Molecular Medicine, School of Medicine, Kagoshima University, Kagoshima, Japan

Requests for reprints: Shinichi Ueno, Department of Surgical Oncology and Digestive Surgery, Field of Oncology, Course of Advanced Therapeutics, Kagoshima University Graduate School of Medicine and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890, Japan. Phone: 81-99-275-5361; Fax: 81-99-265-7426; E-mail: ueno1{at}m.kufm.kagoshima-u.ac.jp.

Purpose: 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.

Experimental Design: 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 B, 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 B activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.

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