Inhibitory effect of the peptide epitalon on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice

Abstract

Female FVB/N HER-2/neu transgenic mice from the age of 2 months were subcutaneously injected with saline, the peptide Epitalonா (Ala-Glu-Asp-Gly) or with the peptide Vilonா (Lys-Glu) in a single dose of 1 g/mouse for 5 consecutive days every month. Epitalon treatment reduced the cumulative number and the maximum size of tumors (p < 0.05). Furthermore, the number of mice bearing 1 mammary tumor was increased, whereas the number of mice bearing 2 or more mammary tumors was reduced in Epitalon-treated in comparison to saline-treated animals (p < 0.05). The size but not the number of lung metastases was reduced in Epitalontreated compared to saline-treated mice (p < 0.05). The treatment with Vilon produced significant negative effects when compared to the control group, with an increased incidence of mammary cancer development (p < 0.05), a shorter mean latent period of tumors (p < 0.05) and an increased cumulative number of tumors (p < 0.05). A 3.7-fold reduction in the expression of HER-2/neu mRNA was found in mammary tumors from HER-2/neu transgenic mice treated with Epitalon compared to control animals. The expression of mRNA for HER-2/neu was also partially reduced in Vilon-treated mice, but it remained significantly higher in Vilon-than in Epitalon-treated animals (1.9-fold increase). The data demonstrate the inhibitory effect of Epitalon in the development of spontaneous mammary tumors in HER-2/ neu mice, suggesting that a downregulation of HER-2/neu gene expression in mammary adenocarcinoma may be responsible, at least in part, for the antitumor effect of the peptide. © 2002 Wiley-Liss, Inc. Key words: peptide; HER-2/neu; transgenic mice; mammary cancerBreast cancer is one of the most common cancers and is a leading cause of mortality in women. 1,2 The HER-2/neu oncogene encodes a 185 kDa (p 185) receptor protein belonging to the epidermal growth factor receptor family involved in organogenesis and epithelial differentiation. 3 Amplification and mutation of HER-2/neu plays a pathogenetic role in several malignancies, including carcinoma of the breast, ovary and uterus. 4,5 Overexpression of ErbB-2/HER-2/neu occurs in 15-40% of human breast cancers. 6 Its appearance correlates with poor prognosis, and it is, therefore, an important target for physiologic investigation and therapeutic intervention. 5 It has been shown that treatment with the pineal indole hormone melatonin inhibits the development of mammary gland tumorigenesis both in vitro and in vivo. [7][8][9][10] It was also shown that the polypeptide pineal preparation Epithalamin inhibits both the growth of transplantable mammary tumors and the development of spontaneous mammary tumors in female C3H/Sn and SHR mice and mammary carcinogenesis induced by 7,12-dimethylbenzanthracene mammary tumors or by total-body X-ray irradiation in female rats. 11-13 Clinical use of Epithalamin was shown to be effective for the treatment of ovarian disturbances and of some types of cancer, breast cancer included. 14 However, the in vivo use of Epithalamin has been rathe...

Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice

“…Petrov Research Institute of Oncology. 44 The animals were kept 5-7 in polypropylene cages (30 x 21 x 10 cm) under a standard light/dark regimen (12 h light: 12 h darkness) at temperature 22 ± 2°C and received standard laboratory chow 43,50 and tap water ad libitum. Animals were checked daily by animal care personnel and weekly by a veterinarian.…”

Peptide bioregulation of aging: results and prospects

“…On the molecular level, there was an obvious gap between multiple evidence of specific effects, caused by regulatory peptides in activation of gene transcription (Khavinson et al 2002a, c;Anisimov and Khavinson 2003;Sibarov et al 2002Anisimov et al 2003Djeridane et al 2003;Kossoy et al 2003;Khavinson and Morozov 2003;Labunets et al 2004a, b), and limited schemes of the process underlying the selective binding of the transcription factor with specific DNA sites. Meanwhile non-specific binding of proteins with the DNA double helix was proved using physicochemical methods (Riadnova et al 2000).…”

Effect of resveratrol on the development of spontaneous mammary tumors in HER‐2/neu transgenic mice

“…Although these results do not exclude the possibility that Res may also influence HER-2/ neu expression at the level of the MMTV promoter, they demonstrate that an MMTV-independent HER-2/neu modulation is feasible. In any case, the possibility that Res may in vivo modulate endocrine pathways that in turn may act on HER-2/neu expression cannot be excluded, as suggested, e.g., by the inhibitory effect exerted by the pineal peptide epitalon on HER-2/neu expression and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice that has been found 35 and that is similar to the antitumor action of Res.…”