Body weight gain and control: beneficial effect of extra virgin olive oil versus corn oil in an experimental model of mammary cancer.

Obesity is a known risk factor for breast cancer, the most common malignancy among women worldwide. We have previously described different effects of high-fat diets on mammary experimental carcinogenesis. In this work, we analyzed the animal growth data obtained in six experimental assays, in healthy and carcinogen-induced rats undergoing different dietary interventions. The animals were fed with three experimental diets administered at different periods of development: a control low-fat diet, and two isocaloric high-fat diets (rich in corn oil or in extravirgin olive oil -EVOO-). Weekly weight throughout the development of 818 animals have been compiled and reanalyzed using adjusted mathematical models. Molecular mechanisms have been investigated: ethanolamides in small intestine, neuropeptides controlling satiety in hypothalamus, and proteins controlling lipid metabolism in adipose and mammary tissues. The results indicated that the effect of diets depended on type of lipid, timing of intervention and health status. The high corn oil diet, but not the high EVOO diet, increased body weight and mass, especially if administered from weaning, in healthy animals and in those that received a moderate dose of carcinogen. The potential protective effect of EVOO on weight maintenance may be related to anorexigenic neuropeptides such as oxytocin and lipolysis/deposition balance in adipose tissue (increasing phospho-PKA, HSL, MGL and decreasing FAS). In animals with cancer, body weight gain was related to the severity of the disease. Taken together, our results suggest that EVOO has a beneficial effect on body weight maintenance in both health and cancer.

The Role of Cancer and Somatic Stem Cells in the Anti-Inflammatory and Antitumor Effects of Aconitum baicalense Extract on Experimental Breast Cancer.

We studied the effects of the extract of the terrestrial part of Aconitum baicalense in BALB/c female mice at the early stages after the injection of N-methyl-N-nitrosourea (MNU). The extract reduced inflammatory activity and tumor growth in the mammary gland. The antitumor and anti-inflammatory effects of the extract are based on the inhibition of cancer stem cells, hematopoietic stem cells, and hematopoietic progenitor cells that promote inflammation. The extract of A. baicalense disrupted the recruitment of epithelial progenitor cells and angiogenesis precursors to the mammary gland preventing neovascularization and transformation of epithelial cells into tumor cells.

Herbal Honey Preparations of Curcuma Xanthorriza and Black Cumin Protect against Carcinogenesis through Antioxidant and Immunomodulatory Activities in Sprague Dawley (SD) Rats Induced with Dimethylbenz(a)anthracene.

BACKGROUND: Traditionally, Curcuma xanthorriza (CX), black cumin seed (BC), and honey have been used by the Indonesian people as medicinal ingredients to treat various health symptoms. CX extracts and BC have been proven in the laboratory as chemopreventive agents, antioxidants, and immunomodulators. In this study, we developed CX extract, BC oil, and honey into herbal honey preparations (CXBCH) and hypothesized that the preparations show chemopreventive activity. The purpose of the study was to determine the CXBCH potential as chemopreventive, antioxidant, and immunomodulatory. METHOD: In this experimental laboratory research, antioxidant, immunomodulatory, and cytotoxic activities were tested on human mammary cancer cell lines (T47D cells) while the chemopreventive activity of the CXBCH preparations on Sprague Dawley (SD) rats induced with dimethylbenzene(a)anthracene (DMBA). RESULTS: CXBCH preparations demonstrated immunomodulatory, antioxidant, and cytotoxic activities in T47D, Hela, and HTB-183 cells and in DMBA-induced SD rats, as the preparations inhibited tumor nodule formation, increased the number of CD4, CD8 and CD4CD25 cells, and glutathione-S-transferase (GST) activity, and decreased serum NO levels. CONCLUSIONS: CXBCH preparations display chemopreventive, antioxidant, and immunomodulatory properties.

Zingiberene exerts chemopreventive activity against 7,12-dimethylbenz(a)anthracene-induced breast cancer in Sprague-Dawley rats.

Breast cancer is the primary cause of cancer-related death in females, wherein increased mortality of breast cancer patients is recorded worldwide. Zingiberene is a monocyclic sesquiterpene from the ginger plant and has many pharmacological benefits. In this exploration, we assessed the anticancer actions of Zingiberene against the 7,12-dimethylbenz(a)anthracene (DMBA)-stimulated mammary carcinogenesis in rats and MDA-MB-231 cells. Breast cancer was induced in the Female Sprague-Dawley rats through the 25 mg/kg of DMBA in 0.5 ml of corn oil and then treated with 20 and 40 mg/kg of Zingiberene, respectively. The body weight of animals and tumor volume was measured. Hematological parameters, transaminases, lipid profile, lipid peroxidation, and antioxidants status were scrutinized using standard techniques. The estrogen receptor-α and inflammatory markers were inspected by using respective assay kits. Histological damage scores were determined. In vitro experiments were conducted to scrutinize Zingiberene's effect on cell viability and apoptotic cell death in MDA-MB-231 cells. Zingiberene substantially modulated the DMBA-stimulated physiological and hematological changes and decreased the transaminases, and lipid peroxidation in the DMBA-stimulated animals. Zingiberene also elevated the antioxidant level and suppressed the inflammatory markers. Histological study revealed the protective effects of Zingiberene. The viability of MDA-MB-231 cells was noticeably diminished by the Zingiberene, thus inducing apoptotic cell death. Overall, our findings reliably proved the anticancer potential of Zingiberene against the DMBA-stimulated mammary tumorigenesis, and it could be a promising chemotherapeutic agent.

Investigation of the Anticancer Effect of α-Aminophosphonates and Arylidine Derivatives of 3-Acetyl-1-aminoquinolin-2(1H)-one on the DMBA Model of Breast Cancer in Albino Rats with In Silico Prediction of Their Thymidylate Synthase Inhibitory Effect.

Breast cancer is a major cause of death in women worldwide. In this study, 60 female rats were classified into 6 groups; negative control, α-aminophosphonates, arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, DMBA, DMBA & α-aminophosphonates, and DMBA & arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. New α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one were synthesized and elucidated by different spectroscopic and elemental analysis. Histopathological examination showed marked proliferation of cancer cells in the DMBA group. Treatment with α-aminophosphonates mainly decreased tumor mass. Bcl2 expression increased in DMBA-administered rats and then declined in the treated groups, mostly with α-aminophosphonates. The level of CA15-3 markedly declined in DMBA groups treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. Gene expression of GST-P, PCNA, PDK, and PIK3CA decreased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one, whereas PIK3R1 and BAX increased in the DMBA group treated with α-aminophosphonates and arylidine derivatives of 3-acetyl-1-aminoquinolin-2(1H)-one. The molecular docking postulated that the investigated compounds can inhibt the Thymidylate synthase TM due to high hydrophobicity charachter.

Preventive Effect of Combined Zingiber officinale and Terminalia chebula against DMBA-Induced Breast Cancer Rats via mTOR Inhibition.

Zingiber officinale (ZO) and Terminalia chebula (TC) are plants used for the treatment of diverse illnesses in traditional medicine. The present study investigates the preventive effect of Zingiber officinale-Terminalia chebula extract (ZOTC) against DMBA-induced breast cancer in a rat model. Bioactive compounds from ZO (6-gingerol, 6-shogaol) and TC (gallic acid, ellagic acid, corilagin, chebulinic acid, and chebulagic acid) were detected using high-performance liquid chromatography. Mammary carcinogenesis was induced in rats with a single subcutaneous injection of 7,12-Dimethylbenz[a]anthracene (DMBA). Oral administration of ZOTC ameliorated the antioxidant status in mammary tissues, serum lipid levels, and serum cytokines. Histological analysis of the mammary tissue (normal and tumor) was carried out to obtain pathological alterations due to ZOTC treatment. The effect of ZOTC on the mechanistic target of rapamycin (mTOR) gene and accumulation of corresponding gene product was also investigated. mTOR plays a central role in cell metabolism and proliferation in normal and cancer cells. Transcriptional and immunohistochemical analysis showed the downregulation of mTOR expression in the mammary tissues of ZOTC-treated rats. In conclusion, the results obtained suggest that ZOTC can suppress tumor progression in DMBA-induced breast cancer rats via inhibition of the mTOR pathway.

Attenuation of Tumor Development in Mammary Carcinoma Rats by Theacrine, an Antagonist of Adenosine 2A Receptor.

Caffeine has been reported to induce anti-tumor immunity for attenuating breast cancer by blocking the adenosine 2A receptor. Molecular modeling showed that theacrine, a purine alkaloid structurally similar to caffeine, might be an antagonist of the adenosine 2A receptor equivalent to or more effective than caffeine. Theacrine was further demonstrated to be an effective antagonist of the adenosine 2A receptor as its concurrent supplementation significantly reduced the elevation of AMPK phosphorylation level in MCF-7 human breast cells induced by CGS21680, an agonist of adenosine 2A receptors. In an animal model, the development of mammary carcinoma induced by 7,12-Dimethylbenz[a]anthracene in Sprague-Dawley rats could be attenuated by daily supplement of theacrine of 50 or 100 mg/kg body weight. Both expression levels of cleaved-caspase-3/pro-caspase-3 and granzyme B in tumor tissues were significantly elevated when theacrine was supplemented, indicating the induction of programmed cell death in tumor cells might be involved in the attenuation of mammary carcinoma. Similar to the caffeine, significant elevation of interferon-γ and tumor necrosis factor-α was observed in the serum and tumor tissues of rats after the theacrine supplement of 50 mg/kg body weight. Taken together, theacrine is an effective antagonist of adenosine 2A receptors and possesses great potential to be used to attenuate breast cancer.

Cumin Prevents 17ß-Estradiol-Associated Breast Cancer in ACI Rats.

Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC.

Effect of Genistein Supplementation on the Progression of Neoplasms and the Level of the Modified Nucleosides in Rats With Mammary Cancer.

BACKGROUND/AIM: The aim of the study was to assess the impact of nano-, micro-, and macro-sized-genistein on the growth and development of neoplasms in rats with mammary cancer. Additionally, the effect on the kinetics of changes (9-11-17-20 week of a rat's life) in the levels of methyl derivatives: 1-methyladenine, 3-methyladenine, 7-methylguanine, 1-methylguanine, 1-methyladenosine, 7-methylguanosine, O-methyl-guanosine and N6-methyl-2'-deoxyguanosine in the urine of rats was analyzed. MATERIALS AND METHODS: Female Sprague-Dawley rats divided into 4 groups were used in the study. Animals were fed only a control diet or diets supplemented with the nano-, micro- and macro-sized genistein. To induce the mammary adenocarcinoma, rats were treated with 7,12-dimethylbenz[a]anthracene (DMBA). Modified nucleosides were determined by a high-performance liquid chromatography coupled to mass spectrometry method (LC-MS/MS). RESULTS: The supplementation of the diet of animals with genistein resulted in an increase in the excretion of methylated derivatives in the urine of rats. In the animals receiving standard diet, the levels of methyl derivatives increased during the study or remained relatively low. In the case of animals whose diet was supplemented with the various forms of genistein, the levels of methylated derivatives were very high from the beginning. CONCLUSION: High levels of methyl derivatives can influence carcinogenesis.

Chemopreventive effects of Melastoma malabathricum L. extract in mammary tumor model via inhibition of oxidative stress and inflammatory cytokines.

The objective of this study was to evaluate the anticancer effects of Melstoma malabathricum L. (MM) MDA-MB-231 human breast cancer and in vivo mammary tumor model and decipher the potential mechanism. The phyto-constituents in the extract have been identified by liquid chromatography-mass spectrometry (LC-MS). The anti-cancer activity of MM extract was tested on MDA-MB-231 human breast cancer cells. Chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) was used for the induction of breast cancer in rodents. Burden, volume, tumor incidence, pro-inflammatory cytokines, antioxidant parameters and mitochondrial parameters were estimated. Histological analysis was determined in mammary gland, vagina, uterus, heart, liver, lung and renal tissues. LC-MS showed the 21 phyto-constituents present in the extract of MM. MM extract showed the potent cytotoxicity against MDA-MB-231 cells and exhibited the IC50 value (14.6 µM). MM extract significantly decreased the body weight and altered the organ weight such as ovary, uterus, liver, spleen, lungs, renal, adrenal and brain tissue. MM extract significantly down-regulated the tumor incidence, tumor burden and average tumor weight at dose dependently manner. MM extract significantly altered the antioxidants activity in term of augmented the level of superoxide dismutase (SOD), catalase (CAT) and suppressed the level of malonaldehyde (MDA); pro-inflammatory cytokines levels such as reduced the level of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) in the serum, hepatic and mammary gland tissue in DMBA induced mammary gland tumor rats. MM extract significantly (P < 0.001) enhanced the activity of mitochondrial parameters include Isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH), Malate dehydrogenase (MDH) and alpha-keto glutaraldehyde dehydrogenase (α-KGDH). The histopathological finding exhibited that MM extract has a marked reduced effect on mammary glands, mammary gland, vagina, uterus, heart, liver, lung and renal.These data provide the scientific evidence that MM extract might be used as a traditional medicine to cure the breast cancer.

A Step Forward in Breast Cancer Research: From a Natural-Like Experimental Model to a Preliminary Photothermal Approach.

Breast cancer is one of the most frequently diagnosed malignancies and common causes of cancer death in women. Recent studies suggest that environmental exposures to certain chemicals, such as 7,12-Dimethylbenzanthracene (DMBA), a chemical present in tobacco, may increase the risk of developing breast cancer later in life. The first-line treatments for breast cancer (surgery, chemotherapy or a combination of both) are generally invasive and frequently associated with severe side effects and high comorbidity. Consequently, novel approaches are strongly required to find more natural-like experimental models that better reflect the tumors' etiology, physiopathology and response to treatments, as well as to find more targeted, efficient and minimally invasive treatments. This study proposes the development and an in deep biological characterization of an experimental model using DMBA-tumor-induction in Sprague-Dawley female rats. Moreover, a photothermal therapy approach using a near-infrared laser coupled with gold nanoparticles was preliminarily assessed. The gold nanoparticles were functionalized with Epidermal Growth Factor, and their physicochemical properties and in vitro effects were characterized. DMBA proved to be a very good and selective inductor of breast cancer, with 100% incidence and inducing an average of 4.7 tumors per animal. Epigenetic analysis showed that tumors classified with worst prognosis were hypomethylated. The tumor-induced rats were then subjected to a preliminary treatment using functionalized gold nanoparticles and its activation by laser (650-900 nm). The treatment outcomes presented very promising alterations in terms of tumor histology, confirming the presence of necrosis in most of the cases. Although this study revealed encouraging results as a breast cancer therapy, it is important to define tumor eligibility and specific efficiency criteria to further assess its application in breast cancer treatment on other species.

Therapeutic effect of Aegle marmelos fruit extract against DMBA induced breast cancer in rats.

Breast cancer is among most common form of cancer worldwide. It is also the major cause of death in female cancer patient around the world. Despite various therapeutic measures, it remains associated with high mortality rate. Aegle marmelos (L.) Correa has been extensively used in Indian medicine system Ayurveda, due to its various medicinal properties. However, there are very limited reports regarding its anticancer activity. Thus, the present research work has been aimed to study the anticancer activity of Aegle marmelos fruit extract on 7,12-dimethylbenz(a)anthracene (DMBA) induced breast cancer in rats. Female Charles Foster rats, 55-60 days old weighing around (150 ± 10 g) were used for the study and were induced DMBA (20 mg/mL dissolved in Olive oil) orally. After the development of breast tumors (about 0.5 cm), the rats were treated with Aegle marmelos ethanolic fruit pulp extract (200 mg/kg b.w./day) orally for 5 weeks and then volume of tumor was measured. Aegle marmelos treatment showed significantly reduced mammary tumor volume (P < 0.05), along with significant reduction (P < 0.0001) in the different serum biomarkers such as TNF-α level, serum malondialdehyde (MDA) level and glucose levels. Significant (P < 0.0001) improvement in both, the kidney and liver serum biomarker parameters were also observed after the treatment with Aegle marmelos ethanolic fruit pulp extract. From the entire study, taking everything into account it can be interpreted that Aegle marmelos ethanolic fruit pulp extract possesses anti-proliferative activity by suppressing the progression of breast tumors in rat model. The plant extract also possesses hepato-renal protective effect. Hence, it can be targeted as novel and safe anti-cancer drug against breast cancer.

Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer.

Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2- BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.

The Essential Oil of Cymbopogon citratus Stapt and Carvacrol: An Approach of the Antitumor Effect on 7,12-Dimethylbenz-[α]-anthracene (DMBA)-Induced Breast Cancer in Female Rats.

C. citratus essential oil and carvacrol have shown an antitumor effect on breast tumor cell lines; the main objective of this research was to evaluate the antitumor effect of the essential oil of Cymbopogon citratus (EOCc) and carvacrol on 7,12-dimethylbenz [a] anthracene (DMBA)-induced breast cancer in female rats. Cancer was induced by a single administration of DMBA at dose of 80 mg/kg body weight (BW). A total of 54 female Holtzman rats were randomly assigned into 9 groups (n = 6). Group I: PS (Physiological saline); Group II: DMBA; Groups III, IV, and V: DMBA + EOCc at doses of 50, 100 and 200 mg/kg/day BW, respectively; Groups VI, VII, and VIII: DMBA + carvacrol at doses of 50, 100 and 200 mg/kg/day BW, respectively; and group IX: DMBA + EOCc + carvacrol at doses of 100 mg/kg/day BW. The treatment lasted 14 weeks. As results, EOCc showed a reduction in tumors as well as necrosis and mitosis. Animals treated with carvacrol did not show necrosis, mitosis, or infiltration. Carvacrol at dose of 100 mg/kg/day BW revealed a significant decrease in the cumulative tumor volume down to 0.11 ± 0.05 cm3 compared to 0.38 ± 0.04 cm3 of the DMBA group (p < 0.01). It is concluded that EOCc and carvacrol had an antitumor effect on DMBA-induced breast cancer in female rats.

(-)-Kusunokinin inhibits breast cancer in N-nitrosomethylurea-induced mammary tumor rats.

Natural and synthetic (-)-kusunokinin inhibited breast cancer, colon cancer and cholangiocarcinoma cells at the G2/M phase and induced apoptosis. However, there is no report on the action and adverse effects of (-)-kusunokinin in animal models. In this study, we investigated the cytotoxic effect of (-)-kusunokinin from Piper nigrum on cancer cells. NMU-induced rat mammary tumors, an ER positive breast cancer model, were treated with (-)-kusunokinin. Proteins of interest related to cell cycle, angiogenesis, migration and signaling proteins were detected in tumor tissues. Results showed that (-)-kusunokinin exhibited strong cytotoxicity against breast, colon and lung cancer cells and caused low toxicity against normal fibroblast cells. For in vivo study, 7.0 mg/kg and 14.0 mg/kg of (-)-kusunokinin reduced tumor growth without side effects on body weight, internal organs and bone marrow. Combination of (-)-kusunokinin with a low effective dose of doxorubicin significantly inhibited tumor growth and provoked cell death in cancer tissues. Mechanistically, 14.0 mg/kg of (-)-kusunokinin decreased cell proliferation (c-Src, PI3K, Akt, p-Erk1/2 and c-Myc), cell cycle (E2f-1, cyclin B1 and CDK1), and metastasis (E-cadherin, MMP-2 and MMP-9) proteins in tumor tissues, which supports its anticancer effect. We further confirmed the antimigration effect of (-)-kusunokinin; the results show that this compound inhibited breast cancer cell (MCF-7) migration in a dose-dependent manner. In conclusion, the results suggest that 14 mg/kg of (-)-kusunokinin inhibited tumors through the reduction of signaling proteins and their downstream molecules. Therefore, (-)-kusunokinin becomes an intriguing candidate for cancer treatment as it provides a strong potency in cancer inhibition.

Morphological Study of Mesenteric Lymph Nodes in Rats with Experimental Breast Cancer Treated with Fragmented Double-Stranded DNA.

We performed a morphometric analysis of mesenteric lymph nodes in rats with breast cancer induced by administration of N-methyl-N-nitrosourea. The volume of the paracortical zone and the number of mature plasma cells in the medullary sinuses were increased and the volume of lymphoid nodules with germinal centers and the number of macrophages were decreased in the group with tumor resection and chemotherapy in comparison with untreated rats with breast cancer. In rats receiving fragmented human double-stranded DNA in combination with adjuvant therapy, the volume of marginal and medullary sinuses and the number of small lymphocytes and macrophages in the paracortical zone increased in comparison with the group receiving chemotherapy without DNA preparation; the volume of lymphoid nodules with germinal centers returned to the level observed in the intact group; the volume of medullary substance and proliferative activity of cells in the germinal centers and medullary substance decreased, the number of mature plasma cells returned to normal in the medullary substance and decreased in the medullary sinuses.

Conjugated Linoleic Acid Isomers Affect Profile of Lipid Compounds and Intensity of Their Oxidation in Heart of Rats with Chemically-Induced Mammary Tumors-Preliminary Study.

Breast cancer and cardiovascular diseases (CVD) have shared risk factors and mechanisms of pathogenicity, as proven by increased cardiac risk in breast cancer patients receiving anticancerogenic therapies and in cancer survivors. A growing mammary tumor may cause heart injury in cancer patients who have not yet been treated. This study aimed to evaluate the effect of conjugated linoleic acid (CLA) supplementation of female rats with 7,12-dimethylbenz(a)anthracene (DMBA)-induced cancerogenesis on fatty acids (FAs), conjugated FAs (CFAs), malondialdehyde (MDA), cholesterol and oxysterols content in cardiac tissue. FAs, cholesterol and oxysterols contents were determined by gas chromatography coupled with mass spectrometry, while the contents of CFAs and MDA were determined by high performance liquid chromatography with photodiode detection. Our results indicate that both CLA supplementation and the presence of tumors influence the lipid biomarkers of CVD. A significant interaction of both experimental factors was observed in the content of polyunsaturated FAs (PUFAs), n-6 PUFAs and CFAs. CLA supplementation significantly inhibited PUFA oxidation, as evidenced by the lower content of MDA in rats' hearts, while the cancerous process intensified the oxidation of cholesterol, as confirmed by the elevated levels of 7-ketocholesterol in DMBA-treated rats. These results may significantly expand knowledge about CLA properties in terms of the prevention of co-existing non-communicable diseases.

99mTc-Radiolabeled TPGS Nanomicelles Outperform 99mTc-Sestamibi as Breast Cancer Imaging Agent.

D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) is a Food and Drug Administration (FDA) approved biomaterial that can form nanosized micelles in aqueous solution. TPGS micelles stand as an interesting system to perform drug delivery as they can carry lipophilic drugs and overcome P glycoprotein efflux as well. Therefore, TPGS micelles combined with other copolymers have been reported in many cancer research studies as a carrier for therapeutic drugs. Their ability to reach tumoral tissue can also be exploited to develop imaging agents with diagnostic application. A radiolabeling method with 99mTc for TPGS nanosized micelles and their biodistribution in a healthy animal model as well as their pharmacokinetics and radiolabeling stability in vivo was previously reported. The aim of this work was to evaluate the performance of this radioactive probe as a diagnostic imaging agent compared to routinely available SPECT radiopharmaceutical, 99mTc-sestamibi. A small field of view gamma camera was used for scintigraphy studies using radiolabeled TPGS micelles in two animal models of breast cancer: syngeneic 4T1 murine cell line (injected in BALB/c mice) and chemically NMU-induced (Sprague-Dawley rats). Ex vivo radioactivity accumulation in organs of interest was measured by a solid scintillation counter, and a semiquantitative analysis was performed over acquired images as well. Results showed an absence of tumoral visualization in 4T1 model for both radioactive probes by gamma camera imaging. On the contrary, NMU-induced tumors had a clear tumor visualization by scintigraphy. A higher tumor/background ratio and more homogeneous uptake were found for radiolabeled TPGS micelles compared to 99mTc-sestamibi. In conclusion, 99mTc-radiolabeled TPGS micelles might be a potential SPECT imaging probe for diagnostic purposes.

Multi-targeting chemoprevention of Chinese herb formula Yanghe Huayan decoction on experimentally induced mammary tumorigenesis.

BACKGROUND: Development of safe and effective chemopreventive agents is a winning strategy in reducing the morbidity and mortality of breast cancer. The current study was to investigate the mechanism-based chemopreventive potential of a Chinese herb formula Yanghe Huayan (YHHY) Decoction on the classical 7,12-dimethylbenz(a)anthracene (DMBA) induced rat mammary carcinogenesis model. METHODS: Female Sprague-Dawley rats at 42 days of age were orally administered with a human equivalent dose of YHHY Decoction at 0.02 ml/g (10 mg/ml) once daily, starting 1 wk. before and 4 wks following DMBA treatment. Mammary tumor occurrence was monitored every day. The length of time before palpable tumor is examined is defined as tumor-free survival time. High performance liquid chromatography (HPLC) analyses were adopted to identify major chemical compositions of the decoction. Following bioinformatics data mining and experimental analyses were performed to demonstrate the underlying mechanism of action. RESULTS: DMBA animals receiving YHHY Decoction exhibited a significant delay (P = 0.014) and in some animals prevention (P = 0.046) of tumor occurrence without obvious toxicity. Oncogenic myc activation was significantly suppressed in the DMBA-induced rats by the YHHY treatment. Eight major chemical compositions of the decoction were identified and were shown to interfere with multiple tumorigenic pathways simultaneously in the mammary tumors, including inducing tumor apoptosis and up-regulating pro-apoptotic protein Bax and down-regulating anti-apoptotic protein Bcl-2; suppressing abnormal cell proliferation and the MAPK/ERK, PI3K/AKT signalings; blocking neo-angiogenesis and the VEGF/KDR signaling, and inhibiting oxidative stress in the mammary tumors. CONCLUSION: The multi-components and multi-targeting properties of the YHHY Decoction support its use as a potent chemopreventive drug in breast cancer.

Effect of Neoadjuvant and Adjuvant Therapy of Experimental Breast Cancer on the Structure of Mesenteric Lymph Nodes.

The morphometric analysis of mesenteric lymph nodes was carried out in female Wistar rats with chemically induced breast cancer. In control rats with untreated breast cancer, the volume of the system of sinuses increased in parallel with the appearance of morphological signs of suppression of cell-mediated immunity, inhibition of humoral immunity, and macrophage reaction. Against the background of chemotherapy, we observed a decrease in the volume of paracortex and lymphoid nodules, suppression of proliferative activity of lymphoid cells in paracortical and B-cell zone, and a decrease in macrophage content. After resection of breast cancer followed by chemotherapy course, lymph transport activation, widening of the paracortex, enhanced proliferative activity of cells in the paracortex and B-cell zone, and reduced volumes of lymphoid nodules with and without germinal centers and medullary substance were revealed in comparison with rats subjected neoadjuvant chemotherapy.