Cancer Influences the Elemental Composition of the Myocardium More Strongly than Conjugated Linoleic Acids-Chemometric Approach to Cardio-Oncological Studies.

The aim of the study was to verify in a cardio-oncological model experiment if conjugated linoleic acids (CLA) fed to rats with mammary tumors affect the content of selected macro- and microelements in their myocardium. The diet of Sprague-Dawley females was supplemented either with CLA isomers or with safflower oil. In hearts of rats suffering from breast cancer, selected elements were analyzed with a quadrupole mass spectrometer with inductively coupled plasma ionization (ICP-MS). In order to better understand the data trends, cluster analysis, principal component analysis and linear discriminant analysis were applied. Mammary tumors influenced macro- and microelements content in the myocardium to a greater extent than applied diet supplementation. Significant influences of diet (p = 0.0192), mammary tumors (p = 0.0200) and interactions of both factors (p = 0.0151) were documented in terms of Fe content. CLA significantly decreased the contents of Cu and Mn (p = 0.0158 and p = 0.0265, respectively). The level of Ni was significantly higher (p = 0.0073), which was more pronounced in groups supplemented with CLA. The obtained results confirmed antioxidant properties of CLA and the relationship with Se deposition. Chemometric techniques distinctly showed that the coexisting pathological process induced differences to the greater extent than diet supplementation in the elemental content in the myocardium, which may impinge on cardiac tissue's susceptibility to injuries.

Her-2 Breast Cancer Outcomes Are Mitigated by Consuming n-3 Polyunsaturated, Saturated, and Monounsaturated Fatty Acids Compared to n-6 Polyunsaturated Fatty Acids.

Lifestyle habits, such as the consumption of a healthy diet, may prevent up to 30-50% of breast cancer (BC) cases. Dietary fats are of specific interest, as research provides strong evidence regarding the association of dietary fats and BC. However, there is limited research on the role of different types of fats including polyunsaturated (PUFA), monounsaturated (MUFA), and saturated fatty acids (SFA). The objective of this study was to determine the effects of lifelong exposure to various dietary fats on mammary tumour development over a 20-week period. Female heterozygous MMTV-neu (ndl) YD5 mouse models were fed five maternal diets containing (1) 10% safflower oil (n-6 PUFA, control), (2) 3% menhaden oil + 7% safflower oil (marine n-3 PUFA, control), (3) 3% flaxseed + 7% safflower oil (plant-based n-3 PUFA), (4) 10% olive oil (MUFA), or (5) 10% lard (SFA). The primary measures, tumour latency, volume, and multiplicity differed by diet treatment in the following general order, n-6 PUFA > plant n-3 PUFA, SFA, MUFA > marine n-3 PUFA. Overall, these findings show that the quality of the diet plays a significant role influencing mammary tumour outcomes.

Suplementação com imunoestimulante em cadelas com neoplasia mamária maligna: aspectos hematológicos e bioquímicos / Immunostimulant supplementation for bitches with malignant mammary tumor: hematological and biochemical aspects

Os alimentos funcionais têm sido empregados como adjuvantes no tratamento do câncer de mama. Neste estudo avaliaram-se as respostas hematológicas e bioquímicas clínicas à ação de um alimento funcional administrado a cadelas com diagnóstico de neoplasia mamária maligna. Após a mastectomia, 16 cadelas foram divididas em dois grupos: suplementadas (S) e não suplementadas (NS) com um composto comercial contendo Saccharomyces cerevisiae, mananoligossacarídeos e nutracêuticos. Ambos grupos receberam tratamento quimioterápico com doxorrubicina e carboplatina, alternadamente, em intervalos de 21 dias, por oito sessões, totalizando 168 dias de tratamento. As avaliações clínicas e laboratoriais foram realizadas nos momentos de aplicação do tratamento. Os resultados dos perfis hematológico (hemograma, leucograma e plaquetograma) e bioquímico sérico (ureia, creatinina, albumina, bilirrubina total e direta, alanina aminotransferase, fosfatase alcalina e gama glutamiltransferase - GGT) foram analisados pelo teste de Kruskall Wallis. No grupo S comprovou-se elevação do peso corporal e não foram observados transtornos gastrointestinais ou outros sinais de alteração clínica ao longo do tratamento. Diferentemente no grupo NS, ocorreu perda de peso e alterações clínicas, como diarreia e vômito. No quadro hematológico, constatou-se leucopenia por linfopenia no grupo de cadelas NS e preservação do valores dentro dos parâmetros considerados normais para a espécie no grupo S. Dentre todas as variáveis da bioquímica clínica, constatou-se apenas a elevação da atividade sérica da GGT nos animais do grupo NS, sem alterações no grupo S. Conclui-se que cadelas com neoplasia mamária quando suplementadas com com alimento funcional imunoestimulante apresentam melhor condição clínica, hematológica e dos níveis bioquímicos, particularmente da GGT.(AU)

Functional foods have been used as adjuvant for breast cancer treatment of bitches. The aim of the present study was to evaluate hematological and clinical biochemistry response in female dogs diagnosed with malignant mammary tumors and supplemented with functional food. After the mastectomy, 16 bitches were divided into two groups: supplemented (S) and none supplemented (NS) with a commercial product of Saccharomyces cerevisiae, mannanoligosaccharides and nutraceuticals. Chemotherapy with doxorubicin and carboplatin was performed alternately at intervals of 21 days for eight sessions during 168 days of treatment. Clinical and laboratorial assessments was made at the treatment moments. The results of the hemogram (erythrogram, leukogram and platelet count) and serum biochemistry (urea, creatinine, albumin, total and direct bilirubin, alanine aminotransferase, alkaline phosphatase and gamma glutamyltransferase - GGT) were analyzed by Kruskal Wallis test. In the S group, increase body weight was observed, but gastrointestinal disorders or other clinical disorders were not detected over the treatment. In the NS group, loss of weight and clinical disorders were observed. All hematology parameters were normal in the S group; however, leukopenia and lymphopenia were detected in the bitches of the NS group. Among all the clinical biochemistry parameters tested, only serum GGT was increased in the NS group, with no changes in the S group. In conclusion, female dogs with mammary tumor supplemented with immunostimulant functional food have better clinical condition, they demonstrate normal levels of hematological and biochemical exams, particularly GGT.(AU)

Targeted nanogel conjugate for improved stability and cellular permeability of curcumin: synthesis, pharmacokinetics, and tumor growth inhibition.

Curcumin (CUR) is a unique natural compound with promising anticancer and anti-inflammatory activities. However, the therapeutic efficacy of curcumin was challenged in clinical trials, mostly due to its low bioavailability, rapid metabolism, and elimination. We designed a nanodrug form of curcumin, which makes it stable and substantially enhances cellular permeability and anticancer activity at standard oral administration. Curcumin was conjugated as an ester to cholesteryl-hyaluronic acid (CHA) nanogel that is capable of targeted delivery to CD44-expressing drug-resistant cancer cells. CHA-CUR nanogels demonstrated excellent solubility and sustained drug release in physiological conditions. It induced apoptosis in cancer cells, suppressing the expression of NF-κB, TNF-α, and COX-2 cellular targets similar to free curcumin. Pharmacokinetic/pharmacodynamic (PK/PD) studies also revealed improved circulation parameters of CHA-CUR at oral, i.p. and i.v. administration routes. CHA-CUR showed targeted tumor accumulation and effective tumor growth inhibition in human pancreatic adenocarcinoma MiaPaCa-2 and aggressive orthotropic murine mammary carcinoma 4T1 animal models. CHA-CUR treatment was well-tolerated and resulted in up to 13-fold tumor suppression, making this nanodrug a potential candidate for cancer prevention and therapeutic treatment.

Dietary selenium supplementation modifies breast tumor growth and metastasis.

The survival rate for breast cancer drops dramatically once the disease progresses to the metastatic stage. Selenium (Se) is an essential micronutrient credited with having high anticancer and chemopreventive properties. In our study, we investigated if dietary Se supplementation modified breast cancer development in vivo. Three diets supplemented with sodium selenite, methylseleninic acid (MSA) or selenomethionine (SeMet), as well as a Se-deficient and a Se-adequate diet were fed to mice before mammary gland inoculation of 4T1.2 cells. The primary tumor growth, the numbers of cancer cells present in lungs, hearts, livers, kidneys and femurs and several proinflammatory cytokines were measured. We found that inorganic selenite supplementation provided only short-term delay of tumor growth, whereas the two organic SeMet and MSA supplements provided more potent growth inhibition. These diets also affected cancer metastasis differently. Mice fed selenite developed the most extensive metastasis and had an increased incidence of kidney and bone metastasis. On the other hand, mice fed the SeMet diet showed the least amount of cancer growth at metastatic sites. The MSA diet also provided some protection against breast cancer metastasis although the effects were less significant than those of SeMet. The cytokine profiles indicated that serum levels of interlukin-2, interleukin-6, interferon γ and vascular endothelial growth factor were elevated in SeMet-supplemented mice. There was no significant difference in tumor growth and the patterns of metastasis between the Se-deficient and Se-adequate groups. Our data suggest that organic Se supplementation may reduce/delay breast cancer metastasis, while selenite may exacerbate it.

Influence of fatty acid-free diet on mammary tumor development and growth rate in HER-2/Neu transgenic mice.

Numerous investigations have found a relationship between higher risk of cancer and increased intake of fats, while results of clinical studies of fat reduction and breast cancer recurrence have been mixed. A diet completely free of fats cannot be easily administered to humans, but experimental studies in mice can be done to determine whether this extreme condition influences tumor development. Here, we examined the effects of a FA-free diet on mammary tumor development and growth rate in female FVB-neu proto-oncogene transgenic mice that develop spontaneous multifocal mammary tumors after a long latency period. Mice were fed a fatty acid-free diet beginning at 112, 35, and 30 days of age. In all these experiments, tumor appearance was delayed, tumor incidence was reduced and the mean number of palpable mammary tumors per mouse was lower, as compared to standard diet-fed mice. By contrast, tumor growth rate was unaffected in mice fed the fatty acid-free diet. Plasma of mice fed the fatty acid-free diet revealed significantly higher contents of oleic, palmitoleic and 20:3ω9 acids and lower contents of linoleic and palmitic acids. In conclusion, these findings indicate that a FA-free diet reduces tumor incidence and latency but not tumor growth rate, suggesting that a reduction in dietary FAs in humans may have a protective effect on tumorigenesis but not on tumors once they appear.

The inhibition of early stages of HER-2/neu-mediated mammary carcinogenesis by dietary n-3 PUFAs.

SCOPE: We previously demonstrated that lifelong feeding of diets enriched in n-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) significantly inhibits HER-2/neu-mediated mammary tumorigenesis in mice. Of interest is whether dietary n-3 fatty acids exert effects at early stages of mammary carcinogenesis. METHODS AND RESULTS: Seven-week-old female MMTV-HER-2/neu transgenic mice were randomized to AIN-based semipurified diets containing either fish or corn oil at 25% energy. Mice were evaluated at 25, 30, and 35 weeks with analysis of mammary glands for atypical ductal hyperplasia (hematoxylin and eosin), cell proliferation (Ki67 immunostaining), and fatty acid synthase and cyclooxygenase-2 gene expression (qRT-PCR). Tissue fatty acid profiles were quantitated by GC. Atypia grade decreased significantly in mice fed fish oil (p = 0.002). Mammary epithelial cells in mammary glands from mice fed fish oil also had an eightfold lower percentage of Ki67 expression. COX-2 expression in mammary fat-pads significantly decreased in mice fed fish versus corn oil enriched diets. CONCLUSION: Dietary fish oil inhibits atypical ductal hyperplasia at early stages of HER-2/neu-mediated mammary carcinogenesis relative to corn oil diets. This histologic change is associated with suppression of mammary epithelial cell proliferation and decreased COX-2 expression in mammary tissue.

The effect of dietary zinc--and polyphenols intake on DMBA-induced mammary tumorigenesis in rats.

BACKGROUND: The aim of the study was to investigate the effect of dietary supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein, on the effectiveness of chemically induced mammary cancer and the changes in the content of selected elements (Zn, Cu, Mg, Fe, Ca) in tumors as compared with normal tissue of the mammary gland. METHODS: Female Sprague-Dawley rats were divided into study groups which, apart from the standard diet and DMBA (7,12-dimethyl-1,2- benz[a]anthracene), were treated with zinc ions (Zn) or zinc ions + resveratrol (Zn + resveratrol) or zinc ions + genistein (Zn + genistein) via gavage for a period from 40 days until 20 weeks of age. The ICP-OES (inductively coupled plasma optical emission spectrometry) technique was used to analyze the following elements: magnesium, iron, zinc and calcium. Copper content in samples was estimated in an atomic absorption spectrophotometer. RESULTS: Regardless of the diet (standard; Zn; Zn + resveratrol; Zn + genistein), DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn + resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. On the basis of quantitative analysis of selected elements we found--irrespectively of the diet applied--great accumulation of copper and iron, which are strongly prooxidative, with a simultaneous considerable decrease of the magnesium content in DMBA-induced mammary tumors. The combination of zinc supplementation with resveratrol resulted in particularly large differences in the amount of the investigated elements in tumors as compared with their content in normal tissue. CONCLUSIONS: Diet supplementation with zinc and polyphenol compounds, i.e. resveratrol and genistein had no effect on the decreased copper level in tumor tissue and inhibited mammary carcinogenesis in the rat. Irrespectively of the applied diet, the development of the neoplastic process in rats resulted in changes of the iron and magnesium content in the cancerous tissue in comparison with the healthy mammary tissue. The application of combined diet supplementation with zinc ions and resveratrol considerably promoted the rate of carcinogenesis and increased the number of DMBA-induced mammary tumors.

Effects of soy isoflavone and endogenous oestrogen on breast cancer in MMTV-erbB2 transgenic mice.

OBJECTIVE: Soy isoflavone is associated with modification of breast cancer risk. Effects of dietary isoflavone on breast tissue carcinogenesis under varying endogenous oestrogen contexts were investigated. METHODS: Five-week-old mouse mammary tumour virus (MMTV)-erbB2 female transgenic mice (n = 180) were divided into three equal groups: low-, normal- and high-oestrogen groups. Each group was then subdivided into an experimental group (given soybean feed) and a control group (given control feed). RESULTS: In the high-oestrogen environment, breast cancer incidence was significantly lower in the experimental versus the control group, whereas in the low-oestrogen environment, breast cancer incidence was significantly higher in the experimental versus the control group. There were no between-group differences in mean breast tumour latency, mean largest tumour diameter and breast tumour tissue vascular endothelial growth factor levels. CONCLUSIONS: Dietary soy isoflavones promote breast cancer at low oestrogen levels but inhibit breast cancer at high oestrogen levels. This effect may only occur during the initiation stage of breast cancer.

A high-throughput pharmaceutical screen identifies compounds with specific toxicity against BRCA2-deficient tumors.

PURPOSE: Hereditary breast cancer is partly explained by germline mutations in BRCA1 and BRCA2. Although patients carry heterozygous mutations, their tumors have typically lost the remaining wild-type allele. Selectively targeting BRCA deficiency may therefore constitute an important therapeutic approach. Clinical trials applying this principle are underway, but it is unknown whether the compounds tested are optimal. It is therefore important to identify alternative compounds that specifically target BRCA deficiency and to test new combination therapies to establish optimal treatment strategies. EXPERIMENTAL DESIGN: We did a high-throughput pharmaceutical screen on BRCA2-deficient mouse mammary tumor cells and isogenic controls with restored BRCA2 function. Subsequently, we validated positive hits in vitro and in vivo using mice carrying BRCA2-deficient mammary tumors. RESULTS: Three alkylators-chlorambucil, melphalan, and nimustine-displayed strong and specific toxicity against BRCA2-deficient cells. In vivo, these showed heterogeneous but generally strong BRCA2-deficient antitumor activity, with melphalan and nimustine doing better than cisplatin and the poly-(ADP-ribose)-polymerase inhibitor olaparib (AZD2281) in this small study. In vitro drug combination experiments showed synergistic interactions between the alkylators and olaparib. Tumor intervention studies combining nimustine and olaparib resulted in recurrence-free survival exceeding 330 days in 3 of 5 animals tested. CONCLUSIONS: We generated and validated a platform for identification of compounds with specific activity against BRCA2-deficient cells that translates well to the preclinical setting. Our data call for the re-evaluation of alkylators, especially melphalan and nimustine, alone or in combination with the poly-(ADP-ribose)-polymerase inhibitors, for the treatment of breast cancers with a defective BRCA pathway.

Effects of dietary energy repletion and IGF-1 infusion on the inhibition of mammary carcinogenesis by dietary energy restriction.

Dietary energy restriction (DER) is a potent inhibitor of mammary carcinogenesis, but the responsible mechanisms are not fully understood. In a number of model systems, DER is associated with a decrease in circulating levels of IGF-1. Moreover, we have recently reported that protection against cancer is lost, and plasma IGF-1 levels are restored to control values when animals are re-fed, i.e., energy repleted (DER-REP). Accordingly, an experiment was designed to determine if infusion of IGF-1 could mimic the effect of DER-REP on the carcinogenic response in animals that were DER. Following 1-methyl-1-nitrosourea injection (50 mg/kg), rats were fed either ad libitum (AL) or 40% DER. After 6 wk, the DER group was divided into three groups: (1) continued DER, (2) DER-REP, or (3) continued DER and infused with 120 mug rh-IGF-1/d (INF) for a duration of 8 d. DER reduced mammary cancer incidence and multiplicity (P < 0.01) versus AL rats. In rats that were DER-REP, cancer incidence increased 1.4-fold and multiplicity increased by 3.6-fold versus DER rats. Plasma IGF-1 were reduced by DER (P < 0.01), an effect that was reversed by DER-REP (P < 0.05). INF increased plasma IGF-1 versus DER rats (P < 0.01) but did not reverse the carcinogenic response. Plasma IGFBP-3 levels were reduced by DER (P < 0.01), but elevated by either REP or INF. Thus, an 8-d period of refeeding following chronic DER (DER-REP) reversed the anticancer effects of DER, and 8 d of IGF-1 infusion without refeeding (INF) did not mimic the effects of the DER-REP on the carcinogenic response.

Relative contribution of calories from dietary fat, carbohydrate, and fiber in the promotion of DMBA-induced mammary tumors in Sprague-Dawley rats.

It is well known that caloric restriction inhibits, whereas excess calories promote, mammary tumorigenesis in rats. However, the relative contribution to carcinogenesis by calories derived from fat or from carbohydrate are not well established. To determine the relative effects of calories from fat or from carbohydrate, as well as any interaction of dietary fiber on the promotion of 7,12-dimethylbenz[a]anthracene-induced mammary tumors, we fed isocalorically nine diets containing different ratios of fat, carbohydrate, and fiber to female Sprague-Dawley rats treated with 7,12-dimethylbenz[a]anthracene (30/group). Under conditions of isocaloric consumption, at or near ad libitum feeding, calories from dietary fat had approximately twofold greater promoting effect on final body weight and tumor incidence than calories derived from dietary carbohydrate. Dietary fiber had an inhibitory effect on tumor development, but the effect was evident only in the high-fat groups. Logistic regression analysis of tumor incidence gave beta-coefficient estimates for the relative effects of fat, carbohydrate, and fiber of 0.866, 0.189, and -4.281, respectively. Time-to-tumor analysis by the Weibull model indicated beta-estimates of 3.016, 3.324, and 5.825 for dietary fat, carbohydrate, and fiber, respectively, indicating that fat shortens and fiber increases the length of time to tumor. The statistical model derived from these results also indicates a significant synergistic interaction of dietary fat and carbohydrate on final body weight and tumor incidence.

The effect of flaxseed supplementation on early risk markers for mammary carcinogenesis.

Since lignans have been suggested to have some cancer-protective effects, flaxseed, the most abundant source of lignan precursors, was tested for its effect on early markers of risk for mammary carcinogenesis. Supplementation of a high-fat diet with flaxseed flour (FF) or defatted flaxseed meal (FM) (5% or 10%) reduced the epithelial cell proliferation by 38.8-55.4% and nuclear aberrations by 58.8-65.9% in female rat mammary gland, with optimum effects seen with the 5% FF. These protective effects were accompanied by increases in urinary lignan excretion indicating that they may be related to the ability of flaxseed to provide lignan precursors.