Effects of Roxithromycin on Tumor Necrosis Factor‐Alpha‐Induced Vascular Endothelial Growth Factor Expression in Human Periodontal Ligament Cells in Culture

Oyama, Tohru; Sakuta, Tetsuya; Matsushita, Kazunobu; Maruyama, Ikuro; Nagaoka, Sumiharu; Torii, Mitsuo

doi:10.1902/jop.2000.71.10.1546

Cited by 41 publications

(47 citation statements)

References 49 publications

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“…Nitric oxide causes DNA breaks and enhances DNA mutations, especially in hepatitis C virus -associated hepatocellular carcinoma (27). Because cloning and functional analysis of the human iNOS gene promoter have identified several copies of NF-nB response elements and several copies of activator protein 1 binding sites, roxithromycin could affect the inactivation of iNOS, as reported in the present study and our former studies (9). Furthermore, iNOS and NADPH oxidase are major sources of reactive oxygen species in experimental hepatocarcinogenesis (28).…”

Section: Discussionsupporting

confidence: 67%

“…Many researchers have shown that an important aspect of inflammation is extravasation of neutrophils into tissues (30 -32). Macrolides inhibit the production of many proinflammatory cytokines such as interleukin 1, interleukin 6, interleukin 8, and tumor necrosis factor a, perhaps by suppressing the transcription factor NF-nB or activator protein 1 (9). Inhibition of cytokine production has been observed in vitro and also in bronchoalveolar lavage fluid, which contains less interleukin 8 and fewer neutrophils after treatment with macrolides.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, on tumor angiogenesis, Yatsunami et al (8) reported that roxithromycin at concentrations >20 Amol/L inhibited endothelial cell migration and tube formation. Moreover, we previously reported the strong inhibitory effect of roxithromycin on tumor necrosis factor a, which induces vascular endothelial growth factor expression in human periodontal ligament cells in culture (9). In this mechanism, roxithromycin suppressed activation of transcription factors activator protein 1 and specificity protein 1, which are critical factors in vascular endothelial growth factor transcription.…”

mentioning

confidence: 91%

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

Ueno¹,

Aoki²,

Kubo³

et al. 2005

Clinical Cancer Research

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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 nB, 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 nB activation induced by experimental hepatocarcinogenesis. The data provide additional evidence for the potential use of roxithromycin in treatment of hepatocellular carcinoma prevention.Hepatocellular carcinoma is one of the most common malignancies in the world, especially in Asia and Africa. The vast majority of patients have preexisting cirrhosis at the time they develop hepatocellular carcinoma. Despite many treatments for this disease in recent decades, its long-term therapeutic outcome remains poor. Prevention seems to be the best strategy in lowering the present incidence of the disease. A preventive effect of an acyclic retinoid on the development of a second tumor after ablation of an original tumor has been shown by one group (1, 2). Conflicting results on the potential preventive effect of IFN have also been reported (3-5). To validate and expand the concept of chemoprevention to other therapeutics, the molecular events that contribute to hepatocarcinogenesis in the liver with cirrhosis need to be identified and targeted.It was reported that tumor growth is angiogenesis dependent by the discovery of angiostatin or endostatin, both of which specifically inhibit endothelial proliferation (6, 7). There are several drugs that have angiogenesis inhibitory properties; however, most of these are restricted by excessive toxicity and limited efficacy. Roxithromycin is a new 14-member macrolide antibiotic that has a wide antibacterial spectrum against pathogens and an immunomodulatory effect. Interestingly, on tumor angiogenesis, Yatsunami et al. (8) reported that roxithromycin at concentrations >20 Amol/L inhibited endothelial cell migration and tube formation. Moreover, we previously reported the strong inhibitory effect of roxithromycin on tumor necro...

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 91%

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

Ueno¹,

Aoki²,

Kubo³

et al. 2005

Clinical Cancer Research

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“…Vascularization of tumors requires the release of angiogenic growth factors (eg VEGF, MCP-1) from tumor cells and/or inflammatory cells such as macrophages and neutrophils or in response to pro-inflammatory cytokines (eg TNF). [120][121][122] NF-B regulates the expression of such growth factors and cytokines (VEGF, TNF, MCP-1) necessary for angiogenesis providing another pathway for which inhibition of NF-B may be justified in anti-cancer therapy. [123][124][125][126] …”

Section: Role Of Nf-b In Angiogenesismentioning

confidence: 99%

Nuclear transcription factor-κB as a target for cancer drug development

2002

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Nuclear factor kappa B (NF-B) is a family of inducible transcription factors found virtually ubiquitously in all cells. Since its discovery by Sen and Baltimore in 1986, much has been discovered about its mechanisms of activation, its target genes, and its function in a variety of human diseases including those related to inflammation, asthma, atherosclerosis, AIDS, septic shock, arthritis, and cancer. Due to its role in a wide variety of diseases, NF-B has become one of the major targets for drug development. Here, we review our current knowledge of NF-B, the possible mechanisms of its activation, its potential role in cancer, and various strategies being employed to target the NF-B signaling pathway for cancer drug development.

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“…The VEGF promoter contains AP-1, AP-2, SP-1, and HIF-1 binding sites [6,7]. Hypoxia induces VEGF expression through activation of HIF-1 [7] and AP-1 [8,9], whereas tumor necrosis factor (TNF)-a increases VEGF expression via SP-1 [8,10].…”

Section: Introductionmentioning

confidence: 99%

Platelet‐activating factor‐induced NF‐κB activation enhances VEGF expression through a decrease in p53 activity

Jung

Seo

et al. 2006

FEBS Letters

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We investigated the role of p53 in nuclear factor (NF)-jB dependent, platelet-activating factor (PAF)-induced vascular endothelial growth factor (VEGF) expression. Transfected NF-jB subunits in ECV304 cells increased the tumor necrosis factor-a promoter activity, which was completely inhibited by p53. Transfected p53 increased p53RE promoter activity, which was completely inhibited by NF-jB subunits, indicating that cross-regulation occurs between NF-jB and p53. PAFinduced increase in VEGF expression was correlated with decreased p53 activity. These data suggest that NF-jB-dependency of the PAF-induced increase in VEGF expression is due to decreased p53 activity, which is reciprocally regulated by increased NF-jB activity.

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Effects of Roxithromycin on Tumor Necrosis Factor‐Alpha‐Induced Vascular Endothelial Growth Factor Expression in Human Periodontal Ligament Cells in Culture

Cited by 41 publications

References 49 publications

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

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

Nuclear transcription factor-κB as a target for cancer drug development

Platelet‐activating factor‐induced NF‐κB activation enhances VEGF expression through a decrease in p53 activity

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