The Therapeutic Potential of Curcuma longa (Turmeric) in the Management of Breast Cancer in Female Rats: Mechanisms and Molecular Targets

Protective effects of hesperidin through attenuation of Ki67 expression against 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.

Breast cancer continues to be a significant health problem for women worldwide and remains one of the most common causes of cancer death in developed countries. In developing countries, the incidence of breast cancer has been trending upward and is becoming a major health burden also. This study aimed at investigating the effect of Cucumis callosus fruit extract on the liver function of 7, 12-Dimethylbenz[a]anthracene (DMBA)-induced mammary cancer in female rats. Thirty-six (36) healthy adult female wistar albino rats weighing about 150 to 200g were purchased. They were housed in polypropylene cages under the standard laboratory condition (25 ± 2°C, humidity 60-70 %, 12 hours light / dark cycles). The animals were fed with commercial rat pellet diet and water was provided ad libitum. The rats were acclimatized to laboratory conditions for one week prior to the commencement of the experiment. Cucumis callosus fruit was bought from Jimeta market in Yola, Adamawa state, Nigeria in November 2023. The pulp of fresh Cucumis Callosus fruits were chopped into pieces and dried at room temperature for 3 weeks. The completely dried fruit pulps were ground into powder by using a mortar and pestle then stored. 10 g of the dried fruit powder was successively extracted with 100 ml of methanol for 48hrs. Afterwards it was filtered with white mesh and then with Whatmann No 1 filter paper. The filtrate was concentrated using a rotatory evaporator. The concentrated extracts was stored in small vials and used for further analysis. The rats were organized into 5 groups: Rats in the control group (group 1) were fed with standard diet and water ad libitum. Rats in group 2 were induced with breast cancer by introducing into them 0.01% DMBA intravenously. Rats in group 3 were treated with standard drug and DMBA. Rats in group 4 were treated with DMBA and 100mg/b.wt, while rats in group 5 were treated with DMBA and 200mg/b.wt as treatment. After treatment for 3 weeks, the liver function marker enzymes levels of the rats such as Aspartate transaminase, Alanine transaminase, and alkaline phosphatase, among others were analyzed. The extract group showed similar levels of liver damage markers (AST and ALT) to the healthy control group, suggesting it might help maintain normal liver function despite the cancer. Total protein levels were not significantly affected by DMBA-induced breast cancer or the treatment plans. However, globulin levels showed significant differences, with higher levels in groups with Cucumis callosus extract. The study also found that a 100 mg/b.wt. dose of Cucumis callosus fruit extract may help maintain normal globulin levels in rats with DMBA-induced mammary cancer, but greater doses and conventional treatment regimens did not. The study suggests that Cucumis callosus extract, at a dose of 100 mg/b.wt, may offer protective effects on liver function in female rats with DMBA-induced mammary cancer.

IntroductionThe historical use of black cumin seed (Nigella sativa) dates back centuries, being embedded in Arabian culture and having a long history of unsurpassed medicinal value with versatility to treat a wide range of ailments. Thymoquinone (TQ) is now known to be the primary active constituent of black cumin seed oil (BCS oil) responsible for its medicinal effects and also showing promise for treatment of cancer.Material and methodsIn the current study, we have studied the effects of TQ and BCS oil on tumor markers (MDA, LDH, ALP and AST), histopathological alterations and the regulation of several genes (Brca1, Brca2, Id-1 and P53 mutation) related to breast cancer in female rats induced by 7,12-dimethylbenz[a]anthracene (DMBA) treatment. Rats received a single dose (65 mg/kg b.w.) of DMBA via an intragastric tube to induce breast cancer. Animals that received DMBA were treated orally with 1, 5, 10 mg/kg of TQ or BCS oil via an intragastric tube three times per week for 4 months.ResultsWe found that TQ and then BCS reduced the rate of tumor markers (levels of MDA and LDH as well as ALP and AST activities), inhibited the histopathological alterations and decreased the expression of the Brca1, Brca2, Id-1 and P53 mutations in mammary tissues of female rats induced by DMBA treatment.ConclusionsThe results suggest that TQ and BCS oil exert a protective effect against breast carcinogens. The antioxidant property of TQ and BCS oil is mediated by their actions and investigating other underlying mechanisms merits further studies.

Breast cancer is the most often diagnosed cancer worldwide, with the greatest fatality rate among women in 2021. Santolina chamaecyparissus L. has been shown to successfully inhibit cancer cells&rsquo; proliferation, especially in the human breast adenocarcinoma (MCF-7) cell line. This study&rsquo;s goal was to evaluate the chemopreventive potential of a S. chamaecyparissus aqueous extract (SCE) on N-methyl-N-nitrosourea (MNU)-induced mammary cancer in female rats. This study was approved by the ORBEA under reference 834-e-CITAB-2020. Twenty-eight four-week-old female Wistar rats were divided into four groups: Control, MNU, SCE and SCE+MNU. SCE was supplemented in drinking water (120 &micro;g/mL) ad libitum and replaced every 3 days due to the compounds&rsquo; stability. A total of nineteen compounds were identified in the extract, with myricetin-O-glucuronide and 1,3-O-dicaffeoylquinic acid being the main compounds found. At 50 days of age, the MNU was administered by intraperitoneal route. Humane Endpoint analysis was performed weekly. Induced animals were palpated twice a week. Tumour width (W) and length (L) were weekly measured with a calliper. Tumour volume was also determined [V = (W2 &times; L)/2]. After twenty-one weeks, animals were sacrificed by a ketamine/xylazine overdose. Control and SCE animals did not develop any tumours. In the MNU group, the first tumour appeared during the ninth week; in SCE+MNU, it only appeared in the sixteenth week. No significant differences were found. However, the tumour incidence in SCE+MNU (28.57%) was lower than in MNU (57.14%). The MNU group had a higher mean tumour weight (2.31 &plusmn; 1.13 g) than the SCE+MNU group (0.39 &plusmn; 0.02 g) and a larger mean tumour volume (2.02 &plusmn; 1.23 cm3) than SCE+MNU (0.57 &plusmn; 0.15 cm3) (p &gt; 0.05). Despite the lack of statistically significant differences between groups, the absence of mortality in SCE+MNU, as well as the lower values in each parameter, suggest that Santolina chamaecyparissus has interesting potential as a chemoprotective agent. Histopathological analysis will help understand this extract&rsquo;s impact on oncogenesis.

Exposure of DMBA-treated female rats in a 50-Hz, 50 microTesla magnetic field: effects on mammary tumor growth, melatonin levels, and T lymphocyte activation.

In view of the methodological problems of epidemiological studies on associations between residential and occupational exposures to 50/ 60-Hz magnetic fields (MF) and increased incidence of cancers, laboratory studies are necessary to determine if 50/60-Hz MF can affect cancer development or growth. Recently, it was reported that alternating (50-Hz) MF of low flux density (100 muT) increase tumor growth and progression in a model of breast cancer in female rats in which mammary tumors were induced by the chemical carcinogen 7,12-dimethylbenz\\[a]anthracene (DMBA). The objective of the present study was to determine if a replicate experiment carried out in the same laboratory under the same experimental conditions yields a significant increase in tumor development and growth of similar magnitude. For the MF experiment, a group of 99 female Sprague-Dawley rats was exposed to a homogeneous horizontally polarized MF for 24 h/ d (minus time for weighing, tumor palpation, cage cleaning, cage rotation), 7 d/wk; another group of 99 rats was sham exposed. DMBA was administered intragastricly at a dose of 5 mg/ rat at the first day of exposure and at weekly intervals thereafter up to a total dose of 20 mg/ rat. Duration of MF or sham exposure was 91 d. In both MF-exposed and sham-exposed rats, the first tumors could be recorded 6 wk after the initial DMBA application. At 9 wk after DMBA application, the group of MF-exposed rats exhibited significantly more animals with tumors than the sham-exposed group. This significant difference in the rate of tumor development was observed throughout the subsequent period of exposure. After autopsy, the incidence of macroscopically visible mammary tumors was 62% in controls, but 83% in MF-exposed rats, with the 35% difference between groups being statistically significant. Data substantiate that long-term exposure of DMBA-treated female Sprague-Dawley rats in an alternating MF of low flux density promotes the development and growth of mammary tumors, thus indicating that MF exposure exerts tumor-promoting and/or copromoting effects. Furthermore, the data show that the effects of MF exposure in the DMBA breast cancer model are reproducible if the same experiment is repeated in the same laboratory.

Introduction: Enoxaparin is an anticoagulant medication. Anticoagulation inhibits tumor cell-mediated release of angiogenic proteins and diminishes angiogenic response. Angiogenesis is an important event in various cancers such as breast cancer. Angiogenesis provide oxygen and nutrients to tumor cells and causes tumor progression. The aim of the present study was to evaluate the anti-angiogenesis effect of an enoxaparin cream on breast cancer induced by dimethylbenzanthracene in rats. Methods: In this experimental in vivo study, 50 Wistar female rats were divided into negative control (vehicle), positive control (cream base), and 3 groups with enoxaparin treatment (40, 60, and 80 mg/ml). After one month of treatment along with breast cancer induction by dimethylbenzanthracene, breast tissue samples were isolated and stained with hematoxylin-eosin, and tumor growth suppression rate was calculated. Tumor size (length and width) was measured using a clipper, and the tumor volume was calculated using the following formula: V = (L × W × W)/2, where V is tumor volume, W is tumor width, L is tumor length. The data were analyzed using one-way ANOVA and Tukey’s post hoc test. Results: Tumor suppression was significantly increased in enoxaparin treatment groups compared to the positive control group (40 mg/ml of enoxaparin treated versus positive control group; P = 0.017, 60 mg/ml of enoxaparin treated versus positive control; P = 0.015, 40 mg/ml of enoxaparin treated versus positive control; P = 0.009, 60 mg/ml of enoxaparin treated versus 40 mg/ml of enoxaparin treated; P = 0.019, and 80 mg/ml of enoxaparin treated versus 40 mg/ml of enoxaparin treated; P = 0.011 in a dose-dependent manner. Conclusion: Enoxaparin inhibits breast cancer in a dose-dependent manner. The application of enoxaparin cream in patients with breast cancer may considerably reduce tumor growth.

Consumption of α-lactalbumin as dietary protein offers a beneficial effect on breast cancer development. Breast cancer was developed by gavage administration of single dose of dimethylbenz(a)anthracene (DMBA) in female rats, maintained on AIN-76A diet with either 20% casein or α-lactalbumin (a component of whey protein). All tumors were detected by palpation. After approximately 130 days of DMBA administration, the animals were euthanized. There was a delay in the development of breast tumor in the α-lactalbumin group in comparison to the casein group. The number of tumors per rat was less in the α-lactalbumin group than that in the casein group at any time point up to 130 days after DMBA administration. Also the incidence of tumors and tumor volume was less in the α-lactalbumin group than those in the casein group. The casein group had a mixture of grade I, grade II and grade III tumors whereas the α-lactalbumin group had mostly grade I tumor. Furthermore, the proliferative index was significantly lower in the α-lactalbumin group than that in the casein group.

Carvacrol is a phenol monoterpene found in aromatic plants specially in Lamiaceae family, which has been evaluated in an experimental model of breast cancer. However, any proposed mechanism based on its antitumor effect has not been reported. In our previous study, carvacrol showed a protective effect on 7,12-dimethylbenz[α]anthracene- (DMBA-) induced breast cancer in female rats. The main objective in this research was to evaluate by using in silico study the carvacrol on HER2, PI3Kα, mTOR, hER-α, PR, and EGFR receptors involved in breast cancer progression by docking analysis, molecular dynamic, and drug-likeness evaluation. A multilevel computational study to evaluate the antitumor potential of carvacrol focusing on the main targets involved in the breast cancer was carried out. The in silico study starts with protein-ligand docking of carvacrol followed by ligand pathway calculations, molecular dynamic simulations, and molecular mechanics energies combined with the Poisson–Boltzmann (MM/PBSA) calculation of the free energy of binding for carvacrol. As result, the in silico study led to the identification of carvacrol with strong binding affinity on mTOR receptor. Additionally, in silico drug-likeness index for carvacrol showed a good predicted therapeutic profile of druggability. Our findings suggest that mTOR signaling pathway could be responsible for its preventive effect in the breast cancer.

Whole plant foods are a rich source of a wide range of bioactive functional substances - phytochemicals, with extensive additive and/or synergistic effects within the process of carcinogenesis. Thanks to the growing body of evidence from preclinical studies on their effectiveness and relatively safe toxicological profile, they can be considered a suitable strategy in the prevention or adjuvant therapy of cancer diseases. Our study aimed to compare the antitumor capacity of various mixtures of phytochemicals contained in whole plant functional foods, namely in salvia (Salvia officinalis L.), aronia (Aronia melanocarpa L.), and sea buckthorn (Hippophae rhamnoides L.), in a chemopreventive model of breast cancer in female rats. Phytopharmaceuticals were administered to animals through the diet in three independent experiments using two concentrations: 1) a lower of 0.1% or 0.3% (Groups 0.1 or 0.3), and 2) a 10-fold higher of 1% or 3% (Groups 1 or 3). In the third group, serving as a control (CONT), no phytopharmaceuticals were administered to the animals. After completing each experiment, an analysis of the basic parameters of experimental mammary carcinogenesis and a comprehensive evaluation of well-validated prognostic, predictive, and diagnostic biomarkers used in oncological practice and preclinical research were performed. CS/LC-MS or LC-DAD/MS analysis of phytopharmaceuticals was performed to detect the presence of dominant phytochemicals. A comprehensive analysis of the mechanism of action of plant-based functional foods confirmed their significant antitumor effects in our experimental breast cancer model, which were, however, specific to the phytopharmaceutical used. Phytopharmaceuticals significantly improved parameters of mammary carcinogenesis in vivo - incidence, frequency, latency of tumors, and/or ratio of HG/LG carcinomas. They statistically significantly improved the expression of markers of apoptosis, proliferation, angiogenesis, cancer stem cells, and oncogenic/tumor-suppressor miRNAs. In addition, chemoprevention led to significant modulation of histone chemical modifications and a decrease in methylation of promoter regions of tumor-suppressor genes. By comparing the efficacy of phytopharmaceuticals, we concluded that the presence of specific dominant plant metabolites may favorably influence the prognosis of mammary carcinogenesis. However, further preclinical and clinical research is necessary to confirm these findings, including assessing the potential of these agents as adjuvant therapy alongside standard oncological treatment.

Breast cancer is the most frequent type of invasive cancer in women. However, chemotherapy affects all cells that grow and divide quickly in the body, including cancer and normal cells. On the other hand, Graviola is commonly used as a source of food and has a wide range of bioactive components. In this study, out of 50 albino rats, breast cancer was induced in 40 rats using 7,12-dimethylbenanthracene (DMBA). These rats were subjected to the treatment using Graviola leaves ethanolic extract (GLEE) and 5-Fluorouracil (5-FU) to evaluate the anti-carcinogenic activity and the immunohistochemical changes. A single oral dose of DMBA led to the induction of rats’ breast cancer. Induced mammary tumors were diagnosed, and all were malignant without any benign tumor. Among the malignant tumors, non-invasive, invasive, mixed (invasive and non-invasive), and unclassified malignant tumors were detected. The immunohistochemical analysis showed that estrogen and progesterone receptors revealed negative nuclear expression. However, HER2 receptors score was +3, and Ki-67 revealed 85-90% nuclear stainability, denoting a very high proliferative index. The morphometric analysis revealed that staining reactivities of HER2 and Ki-67 were 60.66 and 89.84%, respectively, and were significantly higher than ER (15.24 %) and PR (15.68%). Genetic studies revealed marked upregulation of P53 with GLEE more than 5-FU while Bcl2 showed down regulation with GLEE more than 5-FU. The quantitative analysis of GLEE phytochemical constituents showed the presence of some bioactive chemical compounds that exhibit many therapeutic activities. Therefore, GLEE improved histological appearance of DMBA induced breast cancer in female rats. Therefore, GLEE could be a promising natural alternative to chemotherapy agents as a potent anticancer.

Background and Aim:Senecio rhizomatus Rusby (SrR) is a medicinal plant of the Asteraceae family and traditionally consumed as infusion in the Andean region from Peru for inflammatory disorders. This study aimed to determine the histopathological changes afforded by SrR in 7, 12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer (BC) in rats.Materials and Methods:An ethanolic extract of SrR aerial parts was prepared by maceration with 96% ethanol, and the chemical components were identified by gas chromatography coupled to mass spectrometry; the antioxidant activity was determined by 1,1-diphenyl-2-picril-hidrazil (DPPH) assay; and the acute toxicity was assessed according to the OCED 423 guidelines. In a pharmacological study, 30 female Holztman rats were distributed randomly into five groups, as follows. Group I: Negative control (physiological serum, 2 mL/kg); Group II. DMBA (80 mg/Kg body weight); and Groups III, IV, and V: DMBA + ethanol extract of SrR at doses of 10, 100, and 200 mg/kg, respectively.Results:The antioxidant activity of the SrR extract against DPPH was 92.50% at 200 mg/mL. The oral administration of SrR at doses of 50, 300, 2000, and 5000 mg/kg did not show any clinical evidence of toxicity or occurrence of death. The groups that received SrR presented a lower frequency of tumors and acumulative tumor volume compared with the DMBA group (p<0.05); the DMBA group exhibited a higher incidence of necrosis and moderate mitosis, up to 66.67% and 100.00%, respectively. Finally, infiltrating carcinoma with extensive tumor necrosis was evidenced.Conclusion:In experimental conditions, the ethanolic extract of SrR had a protective effect in DMBA-induced BC in female rats. Furthermore, the antioxidant activity of its main phytochemicals could be responsible for the effect observed, and SrR seems to be a safe extract in the preclinical phase.

The aim of this study was to evaluate the effect of mesenchymal stem cells as a treatment against breast cancer via modulation TGF-β. Mesenchymal stem cells (MSCs) are recruited to the stroma of cancers. They interact with cancer cells to promote invasion and metastasis or to suppress tumor growth. The unique tumor-homing capacity of MSCs makes them a promising vehicle to deliver various anticancer agents.

Ameliorative effect of Astaxanthin on DMBA-induced breast cancer in female rats: Interplay between Notch-1 and related miRNAs.