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Electrochemically Reduced Water Delays Mammary Tumors Growth in Mice and Inhibits Breast Cancer Cells Survival In Vitro.

ABSTRACT: Electrochemical reduced water (ERW) has been proposed to have beneficial effects on human health due to its rich content of H2 and the presence of platinum nanoparticles with antioxidant effects. Many studies have demonstrated that ERW scavenging properties are able to reduce the damage caused by oxidative stress in different experimental models. Although few in vivo studies have been reported, it has been demonstrated that ERW may display anticancer effects by induction of tumor cells apoptosis and reduction of both angiogenesis and inflammation. In this study, we show that ERW treatment of MCF-7, MDA-MB-453, and mouse (TUBO) breast cancer cells inhibited cell survival in a time-dependent fashion. ERW decreased ErbB2/neu expression and impaired pERK1/ERK2 and AKT phosphorylation in breast cancer cells. In addition, ERW treatment induced apoptosis of breast cancer cell lines independently of the status of p53 and ER and PR receptors. Our in vivo results showed that ERW treatment of transgenic BALB-neuT mice delayed the development of mammary tumors compared to the control. In addition, ERW induced a significant prolongation of tumor-free survival and a reduction in tumor multiplicity. Overall, these results suggest a potential beneficial role of ERW in inhibiting cancer cells growth.

SUBMITTER: Frajese GV

PROVIDER: S-EPMC6196883 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Electrochemically Reduced Water Delays Mammary Tumors Growth in Mice and Inhibits Breast Cancer Cells Survival In Vitro.

Frajese Giovanni Vanni GV Benvenuto Monica M Mattera Rosanna R Giampaoli Saverio S Ambrosin Elena E Bernardini Roberta R Giganti Maria Gabriella MG Albonici Loredana L Dus Ivan I Manzari Vittorio V Modesti Andrea A Mattei Maurizio M Bei Roberto R

Evidence-based complementary and alternative medicine : eCAM 20180926

Electrochemical reduced water (ERW) has been proposed to have beneficial effects on human health due to its rich content of H2 and the presence of platinum nanoparticles with antioxidant effects. Many studies have demonstrated that ERW scavenging properties are able to reduce the damage caused by oxidative stress in different experimental models. Although few in vivo studies have been reported, it has been demonstrated that ERW may display anticancer effects by induction of tum ...[more]

PMID: 30402124

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Project description:IntroductionThe actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression of Mena adenocarcinoma cells enhances invasion and metastasis in xenograft mice. Whether Mena is required for tumor progression is still unknown. Here we report the effects of Mena deficiency on tumor progression, metastasis and on normal mammary gland development.MethodsTo investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivo invasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice.ResultsMena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivo invasion, in vivo motility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching.ConclusionsDeficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena deficiency during development causes defects in invasive processes involved in mammary gland development. These findings suggest that functional intervention targeting Mena in breast cancer patients may provide a valuable treatment option to delay tumor progression and decrease invasion and metastatic spread leading to an improved prognostic outcome.

Project description:NOTCH activation has been recently implicated in human breast cancers, associated with a poor prognosis, and tumor-initiating cells are hypothesized to mediate resistance to treatment and disease relapse. To address the role of NOTCH1 in mammary gland development, transformation, and mammary tumor-initiating cell activity, we developed a doxycycline-regulated mouse model of NOTCH1-mediated mammary transformation.Mammary gland development was analyzed by using whole-mount analysis and by flow cytometry in nulliparous transgenic mice maintained in the presence/absence of doxycycline (or intracellular NOTCH1). Mammary tumors were examined histologically and immunophenotyped by staining with antibodies followed by flow cytometry. Tumors were transplanted into mammary fat pads under limiting dilution conditions, and tumor-initiating cell frequency was calculated. Mammary tumor cells were also plated in vitro in a tumorsphere assay in the presence/absence of doxycycline. RNA was isolated from mammary tumor cell lines cultured in the presence/absence of doxycycline and used for gene-expression profiling with Affymetrix mouse arrays. NOTCH1-regulated genes were identified and validated by using quantitative real-time polymerase chain reaction (PCR). Mammary tumor-bearing mice were treated with doxycycline to suppress NOTCH1 expression, and disease recurrence was monitored.Similar to published studies, we show that constitutive expression of human intracellular NOTCH1 in the developing mouse mammary gland inhibits side branching and promotes luminal cell fate. These mice develop mammary adenocarcinomas that express cytokeratin (CK) 8/18. In vivo limiting-dilution analyses revealed that these mammary tumors exhibit functional heterogeneity and harbor a rare (1/2,978) mammary tumor-initiating cell population. With this dox-regulated NOTCH1 mammary tumor model, we demonstrate that NOTCH1 inhibition results in mammary tumor regression in vivo and prevents disease recurrence in four of six tumors tested. Consistent with the in vivo data, NOTCH1 inhibition reduces mammary tumorsphere activity in vitro. We also identify the embryonic stem cell transcription factor Nanog as a novel NOTCH1-regulated gene in tumorspheres and in mouse and human breast cancer cell lines.These data indicate that NOTCH1 inhibition results in mammary tumor regression in vivo and interferes with disease recurrence. We demonstrate that NOTCH1-transformed mouse mammary tumors harbor a rare mammary tumor-initiating population and that NOTCH1 contributes to mammary tumor-initiating activity. This work raises the possibility that NOTCH therapeutics may target mammary tumor-initiating cells in certain human breast cancer subtypes.

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Electrochemically Reduced Water Delays Mammary Tumors Growth in Mice and Inhibits Breast Cancer Cells Survival In Vitro.

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Electrochemically Reduced Water Delays Mammary Tumors Growth in Mice and Inhibits Breast Cancer Cells Survival <i>In Vitro</i>.

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