Inhibition of Azoxymethane‐initiated Colon Tumor by Bovine Lactoferrin Administration in F344 Rats

Sekine, Kazunori; Watanabe, Emiko; Nakamura, Joe; Takasuka, Nobuo; Kim, Dae Joong; Asamoto, Makoto; Krutovskikh, Vladimir; Baba-Toriyama, Hiroyasu; Ota, Tomohiro; Moore, Malcolm A; Masuda, Michiaki; Sugimoto, Hajime; Nishino, Hoyoku; Kakizoe, Tadao; Tsuda, Hiroyuki

doi:10.1111/j.1349-7006.1997.tb00413.x

Cited by 100 publications

(57 citation statements)

References 13 publications

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“…1,2) Recently, bovine lactoferrin (bLF) was shown to strongly inhibit development of colon aberrant crypt foci (ACF) and tumors induced by azoxymethane in rats without any toxic effects in major organs. 3,4) Similar effects of bLF were also observed on lung, esophagus, tongue and bladder carcinogenesis in rats. [5][6][7] The results so far obtained thus indicate that bLF is a promising chemopreventive agent for carcinogenesis, although the underlying mechanisms remain unclear.…”

Section: Abstract: Lactoferrin -Cyp1a2 -Meiqx -Liver Carcinogenesissupporting

confidence: 55%

Down‐regulation of 2‐Amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx)‐induced CYP1A2 Expression Is Associated with Bovine Lactoferrin Inhibition of MeIQx‐induced Liver and Colon Carcinogenesis in Rats

Fujita

Ohnishi

Sekine

et al. 2002

Japanese Journal of Cancer Research

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The inhibitory influence of bovine lactoferrin (bLF) on induction of preneoplastic hepatic glutathione S-transferase placental form-positive (GST-P + ) cell foci and colon aberrant crypt foci (ACF) by diethylnitrosamine (DEN) and 2-amino-3,8-dimethylimidazo[4,5-f ]quinoxaline (MeIQx) was investigated in F344 rats. Rats were initially treated with DEN, then placed on basal diet containing MeIQx (200 ppm) alone, MeIQx plus 2% bLF, or MeIQx plus 0.2% bLF from week 2 to week 8, with partial hepatectomy performed at week 3. Concomitant administration of 2% or 0.2% bLF with MeIQx caused significant dose-dependent decreases in both number and unit area of GST-P + cell foci (2% bLF, P < < < <0.001; 0.2% bLF, P < < < <0.01). Similar results were observed for MeIQx-induced colon ACF in the groups without DEN treatment (2% and 0.2% bLF, P < < < <0.05). To investigate the underlying mechanisms, we analyzed the influence of bLF on levels of cytochrome P4501A2 (CYP1A2), a metabolically activating enzyme of MeIQx in the liver. The results demonstrated that combined administration of 2% bLF significantly reduced levels of MeIQx-induced CYP1A2 mRNA (P < < < <0.05) and protein (P < < < <0.05) to the normal levels, in association with reduced values for MeIQx-DNA adducts (P < < < <0.05), liver GST-P + cell foci and colon ACF. These results suggest that bLF is a chemopreventive agent for DEN alone or DEN plus MeIQx-induced liver, and MeIQx-induced colon carcinogenesis in rats. One possible mechanism is a normalizing down-regulation of CYP1A2 expression by bLF, with consequent reduction of carcinogen activation and adduct formation.

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Section: Abstract: Lactoferrin -Cyp1a2 -Meiqx -Liver Carcinogenesissupporting

confidence: 55%

Down‐regulation of 2‐Amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx)‐induced CYP1A2 Expression Is Associated with Bovine Lactoferrin Inhibition of MeIQx‐induced Liver and Colon Carcinogenesis in Rats

Fujita

Ohnishi

Sekine

et al. 2002

Japanese Journal of Cancer Research

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“…Recently, we have shown that bLF inhibits the development of AOM-induced aberrant crypt foci (precursor lesions) 9) and carcinomas 10) in the rat colon when given as 20) Furthermore, we have observed activation of NK activity in AOM-treated rats fed bLF. 8) Findings have accumulated pointing to a wide array of functions of bLF in the immune system; thus NK cell activation, 5) stimulation of LAK cell activity 6) and potentiation of macrophage cytotoxicity 7) have been documented, Many compounds have been demonstrated to exert chemopreventive effects.…”

Section: Discussionmentioning

confidence: 71%

“…We have recently shown that dietary supplementation with bovine lactoferrin (bLF), derived from bovine milk, 2) can inhibit the development of azoxymethane (AOM)-induced aberrant crypt foci (ACF) as precursor lesions of tumor development, 9) as well as carcinomas 10) in the rat colon, without any toxic effects in major organs. It was also found to reduce growth and metastasis of solid tumors.…”

mentioning

confidence: 99%

Possible Chemopreventive Effects of Bovine Lactoferrin on Esophagus and Lung Carcinogenesis in the Rat

Ushida

Sekine

Kuhara

et al. 1999

Japanese Journal of Cancer Research

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A milk component, bovine lactoferrin (bLF), previously shown by us to be a strong chemopreventive of colon carcinoma development, was examined for its influence on other organs using a rat multi-organ carcinogenesis model. Male F344 rats, aged 6 weeks, were treated sequentially with diethylnitrosamine (DEN, i.p.), dihydroxy-di-N-propylnitrosamine (DHPN, in drinking water) and N-nitrosomethylbenzylamine (NMBA, s.c.) during the first 8 weeks (DDN treatment), and then bLF was administered in the basal diet, at a dose of 2, 0.2, 0.02 or 0.002%. Other groups were given DDN treatment or bLF alone as controls. All surviving animals were killed at week 41, and major organs were examined histopathologically for neoplastic lesions. In the esophagus, a tendency for reduction in development of papillomas was evident in the bLF-treated animals, along with a significant suppression of relatively large-sized papillomas (more than 50 mm 3 volume) at the 0.2% dose (P< < < <0.05, 11% of the control). The multiplicity of tumors (adenomas and carcinomas) in the lung was also decreased in animals fed 0.02% bLF (1.98± ± ± ±0.41 per cm 2 lung tissue section, P< < < <0.05) compared to the control group (3.48± ± ± ±0.33). No enhancing or inhibitory effects of bLF on tumor development in other organs were noted. The present results indicate that bLF exerts chemopreventive effects in the esophagus and lung in addition to the colon.

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“…Recently, some studies have suggested chemopreventive and antitumor activity for lactoferrin as well. In rat models, lactoferrin treatment significantly reduced azoxymethane-induced colonic carcinogenesis, as well as N-butyl-N- (4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis (2,3). In addition, Bezault et al (4) found that lactoferrin reduced solid tumor growth and strongly inhibited experimental metastasis in mice.…”

Section: Introductionmentioning

confidence: 97%

Lactoferrin Down-Regulates G1 Cyclin-Dependent Kinases during Growth Arrest of Head and Neck Cancer Cells

Yan

Monitto

Minhas

et al. 2004

Clinical Cancer Research

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The molecular mechanism of lactoferrin-induced cell growth inhibition is incompletely understood. Studying head and neck cancer cells treated with human lactoferrin, we observed growth arrest in three of four cell lines tested. This growth arrest was caused by cell cycle inhibition at the G 0 -G 1 checkpoint. Lactoferrin-induced growth inhibition was associated with a large increase in p27 protein, accompanied by decreased phosphorylation of retinoblastoma protein, and suppression of cyclin E. Decreased levels of phosphorylated Akt were also observed in lactoferrin-sensitive cell lines after treatment. These findings suggest that in head and neck cancer cells the growth inhibitory effects of lactoferrin are mediated through a p27/cyclin E-dependent pathway that may be modulated in part by changes in Akt phosphorylation.

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Inhibition of Azoxymethane‐initiated Colon Tumor by Bovine Lactoferrin Administration in F344 Rats

Cited by 100 publications

References 13 publications

Down‐regulation of 2‐Amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx)‐induced CYP1A2 Expression Is Associated with Bovine Lactoferrin Inhibition of MeIQx‐induced Liver and Colon Carcinogenesis in Rats

Down‐regulation of 2‐Amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx)‐induced CYP1A2 Expression Is Associated with Bovine Lactoferrin Inhibition of MeIQx‐induced Liver and Colon Carcinogenesis in Rats

Possible Chemopreventive Effects of Bovine Lactoferrin on Esophagus and Lung Carcinogenesis in the Rat

Lactoferrin Down-Regulates G1 Cyclin-Dependent Kinases during Growth Arrest of Head and Neck Cancer Cells

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