DMBA-induced Mammary Carcinoma Research Articles

“Development, optimization, and characterization of Eudragit-based nanoparticles for Dasatinib delivery”

This study focused on developing and evaluating dasatinib-loaded nanoparticles (DST-NPs) using Eudragit L100 as a polymer matrix for enhanced breast cancer treatment. The optimized formulation exhibited a particle size of 202.1 ± 5.7 nm, a zeta potential of −18 ± 1.01 mV, and an entrapment efficiency of 93.11 ± 0.2%. In-vitro release studies demonstrated sustained drug release from DST-NPs, following Fickian diffusion. Pharmacokinetic studies in rats revealed higher Cmax and AUC0-t for DST-NPs compared to pure DST, indicating improved bioavailability. Tissue distribution studies showed enhanced targeting of DST-NPs, with higher concentrations in the liver and spleen. In vivo efficacy in a DMBA-induced mammary carcinoma model demonstrated that DST-NPs significantly reduced tumor volume, maintained stable body weight, and improved survival rates compared to pure DST. Hematologic analysis indicated a favorable blood profile with DST-NPs, and histopathological examinations confirmed the restoration of normal mammary gland and liver architecture. MTT assays showed higher cytotoxicity of DST-NPs against MCF-7, MDA-MB231, and 4T1 cell lines, with lower IC50 values than pure DST. Stability studies indicated that DST-NPs maintained their properties over six months at various storage conditions. These findings highlight the potential of DST-NPs as an effective nanocarrier system for cancer therapy.

A novel quinazoline derivative exhibits potent anticancer cytotoxicity via apoptosis and inhibition of angiogenesis in DMBA-induced mammary gland carcinoma.

Mammary gland carcinoma is one of the most prevalent and deadly diseases among women globally. It is a type of solid malignant tumor. In this malignant tumor, the microenvironment becomes hypoxic in rapidly proliferating cancer cells. These cells undergo adaptive changes through the expression of hypoxia-inducible factor-1alpha (HIF-1α) which is regulated by factor inhibiting HIF-1α (FIH-1). Considering this, we hypothesized that the chemical activation of FIH-1 would inhibit the hypoxic activity of HIF-1α in mammary gland carcinoma. A library of 67,609 chemical compounds was virtually screened against FIH-1 based on Lipinski's rule from the ZINC database. The BBAP-8 has been selected based on an excellent docking score (-8.352 Kcal/mol), favorable ADMET, and potential FIH-1 activator profile. Further, its in-vitro cytotoxicity and apoptotic activity were scrutinized against MCF-7 cells and in-vivo activity against 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland carcinoma in Wistar rats. It exhibited significant cytotoxicity (IC50 = 16.59 ± 0.49 μM) and activated apoptosis when scrutinized through DAPI, AO/EB, and JC-1 staining. Also, oral administration of BBAP-8 restored hemodynamic changes, normalized tissue architecture, and corrected metabolic abnormalities. The western blot analysis and mRNA expression analysis validated that BBAP-8 has the potential to activate FIH-1 with the downregulation of GLUT-1, VEGF, and Twist-1. Moreover, BBAP-8 fostered apoptosis, when evaluated through BCL-2, BAX, Caspase-8, and Caspase-3. Based on research findings, this implies that BBAP-8 activates FIH-1 and can be effective in chemotherapeutic treatment of mammary gland carcinoma.

Catechin enhances the antitumour activity of Bleomycin in DMBA-induced mammary carcinoma in rats

Catechin enhances the antitumour activity of Bleomycin in DMBA-induced mammary carcinoma in rats

Tenofovir alone or combined with doxorubicin abrogates DMBA-induced mammary cell carcinoma: An insight into its modulatory impact on oxidative/Notch/apoptotic signaling

AimsBreast cancer incidence keeps on growing and emerging as one of the major global challenges, therefore, the introduction of new approaches is of great demand. Drug repurposing is crucial to faster and cheaper discovery of anti-cancer drugs. The antiviral tenofovir disproxil fumarate (TF) was reported to decrease hepatocellular carcinoma risk by interfering with cell cycle and proliferation. This study aimed to scrutinize the role of TF alone or combined with doxorubicin (DOX) in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast carcinoma rat model. Materials and methodsBreast carcinoma was induced by DMBA (7.5 mg/kg, twice/week, subcutaneous into mammary gland) for 4 successive weeks. TF (25 and 50 mg/kg/day) was given orally and DOX (2 mg/kg) was injected once/week by tail vein starting from day 1. Key findingsThe anti-cancerous effect of TF was mediated by suppression of oxidative stress markers and Notch signaling proteins (Notch1, JAG1, and HES1), attenuation of tumor proliferation markers (cyclin-D1 and Ki67), and boosting of apoptosis (P53 and Caspase3) and autophagy biomarkers (Beclin1 and LC3). In parallel, histopathological assessment displayed that mammary glands from animals treated with TF alone or combined with DOX showed better histopathological scores. Interestingly, TF and DOX co-treatment markedly decreased myocardial injury markers (AST, LDH, and CK-MB), restored the balance between GSH and ROS, prohibited lipid peroxidation, and preserved microscopic myocardial architecture. SignificanceTF elicited antitumor activity via multiple molecular mechanisms. Moreover, combining TF with DOX might be a potential novel strategy to enhance DOX-anticancer activity and decrease its cardiac side effects.

Canagliflozin interrupts mTOR-mediated inflammatory signaling and attenuates DMBA-induced mammary cell carcinoma in rats

BackgroundBreast cancer prevalence has been globally increasing, therefore, introducing novel interventions in cancer treatment is of a significant importance. The present study was designed to investigate the anti-cancer effect of Canagliflozin (CNG) in an experimental model of DMBA-induced mammary carcinoma in female rats. Methods18 female rats were divided into three experimental groups: Normal control, DMBA control, DMBA+ CNG treated group. DMBA (7.5 mg/kg) was injected subcutaneously in the mammary cells twice weekly for 4 weeks and CNG (10 mg/kg) was orally administered daily for an additional 3 weeks while DMBA control rats only received the vehicle for 3 weeks. Tumors’ weight and volume were measured, BRCA-1 and TAC were quantified in serum samples, mTOR, caspase-1, NFκB, IL-1β, NLRP3, GSDMD and MDA were quantified in tumors’ homogenates. Results: CNG treatment increased the BRCA-1 expression, suppressed mTOR inflammatory pathway, attenuated tumor inflammatory mediators; NLRP3, GSDMD, NFκB, IL-1β, suppressed the oxidative stress and inhibited tumor expression of the proliferation biomarker; Ki67. ConclusionCNG modulated mTOR-mediated signaling pathway and attenuated pyroptotic, inflammatory pathways, suppressed oxidative stress and eventually inhibited DMBA-induced mammary carcinoma proliferation.

Mesenchymal Stem Cells and Selenium Nanoparticles Synergize with Low Dose of Gamma Radiation to Suppress Mammary Gland Carcinogenesis via Regulation of Tumor Microenvironment

Breast cancer is one of the most prevalent and deadliest cancers among women in the world because of its aggressive behavior and inadequate response to conventional therapies. Mesenchymal stem cells (MSCs) combined with green nanomaterials could be an efficient tool in cell cancer therapy. This study examined the curative effects of bone marrow–derived mesenchymal stem cells (BM-MSCs) with selenium nanoparticles (SeNPs) coated with fermented soymilk and a low dose of gamma radiation (LDR) in DMBA-induced mammary gland carcinoma in female rats. DMBA-induced mammary gland carcinoma as marked by an elevation of mRNA level of cancer promoter genes (Serpin and MIF, LOX-1, and COL1A1) and serum level of VEGF, TNF-α, TGF-β, CA15-3, and caspase-3 with the reduction in mRNA level of suppressor gene (FST and ADRP). These deleterious effects were hampered after treatment with BM-MSCs (1 × 106 cells/rat) once and daily administration of SeNPs (20 mg/kg body weight) and exposure once to (0.25 Gy) LDR. Finally, MSCs, SeNPs, and LDR notably modulated the expression of multiple tumor promoters and suppressor genes playing a role in breast cancer induction and suppression.

CEG-AgNPs Ameliorates DMBA-Induced Mammary Carcinogenicity by Alleviating Cytokines Expression.

<b>Background and Objective:</b> For more than a decade, breast cancer has been one of the most common forms of cancer among women around the world. The present article aimed to evaluate the protective activity of CEG-AgNPs against DMBA-induced mammary carcinoma. <b>Materials and Methods:</b> In this experimental study, green synthesis and characterization of CEG-AgNPs were carried as well as IC<sub>50</sub> against Mcf7 cell line and LD<sub>50</sub> on mice were evaluated. A total of 24 adult albino mice were divided into four groups six rats in each. Group I was given an equal amount of distilled water, group II was received 80 mg kg<sup></sup><sup>1</sup> b.wt., DMBA for 4 weeks, groups III and IV were treated with CEG-AgNPs (28.1 and 70.25 mg kg<sup></sup><sup>1</sup>) from the 5th week of DMBA administration for 4 weeks, respectively. <b>Results:</b> CEG-AgNPs were approximately 42.32±9.52 nm with a negative zeta potential of -17.44. It is IC<sub>50</sub> against the Mcf7 cell line and LD<sub>50</sub> is equal to 82.76 μg mL<sup></sup><sup>1</sup> and 1405 mg kg<sup></sup><sup>1</sup> b.wt., A significant normalization in plasma ALT, AST, AST and LDH as well as mammary MDA, TNF-α, IL-6, P53, SOD, GPx and GSH levels have been observed in CEG-AgNPs treated mice. Oral CEG-AgNPs administration has suppressed VEGF-C gene expression in DMBA-treated mice. <b>Conclusion:</b> The present results, biochemical, histological and MRI results showed that CEG-AgNPs have potent anticancer activity against DMBA-induced mammary carcinoma in mice by inducing the biosynthesizes of antioxidant biomarkers and suppression of cytokines gene expression.

Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia.

The current study investigated the role of combination therapy with voacamine and vincristine in preventing mammary gland carcinoma through prolyl hydroxylase-2 activation. Prolyl hydroxylase-2 activation leads to the downregulation of hypoxia-inducible factor-1α and fatty acid synthase. Overexpression of hypoxia-inducible factor-1α and fatty acid synthase has been previously reported in solid tumors of the mammary gland. After screening a battery of natural compounds similar to vincristine, voacamine was selected as a possible prolyl hydroxylase-2 activator, and its activity was evaluated using a 7,12-dimethylbenz[a]anthracene-induced rat model. The combination therapy was evaluated for cardiac toxicity using a hemodynamic profile. Angiogenic markers were evaluated by carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity using hematoxylin and eosin staining. The antioxidant potential was delineated using oxidative stress markers. The serum metabolomic profile was studied using NMR spectroscopy, and the disruption of fatty acids was evaluated using gas chromatography. Western blotting of proteins involved in hypoxic pathways was performed to decipher the action of therapy at the molecular level. Immunoblotting analysis validated that combination therapy has potential toss with prolyl hydroxylase-2 activity and thus initiates proteolytic degradation of hypoxia-inducible factor-1α and its consequent effects. Combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells. The present study explored the role of voacamine inactivation of prolyl hydroxylase-2, which can decrease the overexpression of hypoxia-inducible factor-1α and fatty acid synthase in mammary gland carcinoma cells.

Novel quercetin encapsulated chitosan functionalized copper oxide nanoparticles as anti-breast cancer agent via regulating p53 in rat model

This study was designed to present a new quercetin encapsulated chitosan functionalized copper oxide nanoparticle (CuO-ChNPs-Q) and assessed its anti-breast cancer activity both in vitro and in vivo. The CuO-ChNPs-Q may act as anti-proliferating agent against DMBA-induced mammary carcinoma in female rats. The CuONPs was functionalized with chitosan then quercetin was conjugated with them producing CuO-ChNPs-Q, then characterized. The in vitro anti-proliferating activity of the CuO-ChNPs-Q was evaluated against three human cell line. Then, the anti-breast cancer effect of the CuO-ChNPs-Q was assessed against DMBA-induction compared to both CuONPs and Q in female rat model. The in vitro results proved the potent anticancer activity of the CuO-ChNPs-Q compared to CuONPs and quercetin. The in vivo data showed significant reduction in breast tumors of DMBA-induced rats treated with CuO-ChNPs-Q compared to CuONPs and Q. The CuO-ChNPs-Q treatment had induced apoptosis via increased p53 gene, arrested the cell-cycle, and increased both cytochrome c and caspase-3 levels leading to mammary carcinoma cell death. Also, the CuO-ChNPs-Q treatment had suppressed the PCNA gene which decreased the proliferation of the mammary carcinoma cells. In conclusion, the CuO-ChNPs-Q might be a promising chemotherapeutic agent for treatment of breast cancer with a minimal toxicity on vital organs.

Exploration of anti-breast cancer effects of Terminalia chebula extract on DMBA-induced mammary carcinoma in Sprague Dawley rats

BackgroundPlant extracts are effectively acting as the natural medicinal cocktail, non-side effective, efficacious, and freely available. The present study aimed to unveil the pharmacological and medicinal effects of Terminalia chebula plant extract in 7,12-dimethylbenzanthracene (DMBA)-induced mammary carcinoma in Sprague Dawley rats. The plant extract obtained was subjected to in vivo antioxidant and anticancer studies in various concentrations after an analytical technique such as FTIR, GCMS, and HPLC-based chemo-profiling in Sprague Dawley rats.ResultsApart from the antiproliferative effect on breast cancer cell line (MCF-7) and normal breast epithelial cells (MCF-10a), we have measured the changes in body weight, along with other tumor parameters such as tumor volume, tumor incidence, tumor weight, tumor burden, serum biochemical parameters, and histopathological findings of breast tissue. As the oxidative stress further enhances the development of cancer, the antioxidant property of the plant extract demonstrates its use against cancer treatment. One hundred fifty milligrams per milliliter (IC50 250 μg/mL) concentration of the ethanolic extract was vital for the proliferation of MCF-7 cell lines (Fig. 7a). Meanwhile, 300 μg/mL (IC50 150 μg/mL) was an effective dose to attain a maximum HDAC inhibition of 78%. Also, the normal liver and kidney functioning revealed the non-toxicity nature of the plant.ConclusionTerminalia chebula could be one of the effective naturally obtained anti-breast cancer medications. Isolation and characterization of individual bioactive compounds of T. chebula would be the future perspective.

RETRACTED ARTICLE: Biotin anchored nanostructured lipid carriers for targeted delivery of doxorubicin in management of mammary gland carcinoma through regulation of apoptotic modulator

We, the Editors and Publisher of the Journal of Liposome Research have retracted the following article: ChandraB. Tripathi, Poonam Parashar, Malti Arya, Mahendra Singh, Jovita Kanoujia, Gaurav Kaithwas & Shubhini A. Saraf (2020). Biotin anchored nanostructured lipid carriers for targeted delivery of doxorubicin in management of mammary gland carcinoma through regulation of apoptotic modulator, Journal of Liposome Research, 30:1, 21-36, DOI: https://doi.org/10.1080/08982104.2019.1579839 Following publication, concerns were raised regarding the integrity of the data in the article. Upon further investigation by the Publisher, in collaboration with the Editors, it was confirmed that there were significant overlaps between the images in Figure 8 of the article and, some of these images had been reused from the authors’ previous publications without appropriate acknowledgement: Manral, C., Roy, S., Singh, M. et al. Effect of β-sitosterol against methyl nitrosourea-induced mammary gland carcinoma in albino rats. BMC Complement Altern Med 16, 260 (2016). https://doi.org/10.1186/s12906-016-1243-5 Roy S, Singh M, Sammi SR, Pandey R, Kaithwas G. ALA-mediated biphasic downregulation of α-7nAchR/HIF-1α along with mitochondrial stress modulation strategy in mammary gland chemoprevention. J Cell Physiol. 2019; 234: 4015–4029. https://doi.org/10.1002/jcp.27168 Roy S., Kumar Rawat A., Raj Sammi S., Devi U., Singh M., Gautam S., Kumar Yadav R., Kumar Rawat J., Singh L., Nazam Ansari M., Saeedan A. S., Pandey R., Kumar D., et al Alpha-linolenic acid stabilizes HIF-1 α and downregulates FASN to promote mitochondrial apoptosis for mammary gland chemoprevention. Oncotarget. 2017; 8: 70049-70071. Retrieved from https://www.oncotarget.com/article/19551/text/ In addition, it was found that this article has significant similarities in text with the authors’ previously published article which has not been referenced appropriately: Tripathi, C.B., Parashar, P., Arya, M. et al. QbD-based development of α-linolenic acid potentiated nanoemulsion for targeted delivery of doxorubicin in DMBA-induced mammary gland carcinoma: in vitro and in vivo evaluation. Drug Deliv. and Transl. Res. 8, 1313–1334 (2018). https://doi.org/10.1007/s13346-018-0525-5 Upon query, the corresponding author has cooperated with the investigation but has not been able to provide a satisfactory explanation for the significant level of overlap in text and data. As this is a serious breach of the journal’s editorial policies, we are retracting the article from the journal. The authors do not agree with the retraction. We have been informed in our decision-making by our editorial policies and the COPE guidelines. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

QbD-based development of α-linolenic acid potentiated nanoemulsion for targeted delivery of doxorubicin in DMBA-induced mammary gland carcinoma: in vitro and in vivo evaluation.

Breast cancer is the most common cancer of occurrence in women and has the highest mortality incidence rate therein. The present study envisaged to develop doxorubicin (Dox) loaded folate functionalized nanoemulsion (NE) for profound therapeutic activity against mammary gland cancer. NE was prepared using pseudo-ternary phase diagrams utilizing α-linolenic acid (ALA) as lipid phase, to further enhance the anticancer potential of Dox. Box-Behnken design was employed to systematically develop the NE. Optimized NE (f-Dox-NE) was evaluated for in vitro and in vivo performance. f-Dox-NE, with globule size 55.2 ± 3.3nm, zeta potential - 31 ± 2mV, entrapment 92.51 ± 3.62%, drug loading 0.42 ± 0.08% and percent drug release 94.86 ± 1.87% in 72h, was capable of reducing cell viability in MCF-7 cell lines vis-à-vis pure and marketed drug. Further, mechanistic studies in MCF-7 cell lines demonstrated that f-Dox-NE induces cellular apoptosis by reactive oxygen species generated and mitochondrial membrane mediated apoptosis. The antitumor effect was evaluated in 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary gland tumor in female Albino Wistar rats. f-Dox-NE exhibited enhanced antitumor targeting potential, therapeutic safety and efficacy vis-à-vis pure and marketed drug, as revealed by tumor volume, animal survival, weight variation, cardiotoxicity and biodistribution studies. f-Dox-NE restored the biochemical parameters viz., SOD, catalase, TBARS and protein carbonyl, towards normal levels in comparison to DMBA induced animal group. f-Dox-NE displayed downregulation of anti-apoptotic (Bcl-2 and MMP-9) proteins and upregulation of pro-apoptotic proteins (caspase-9 and BAX). The experimental results suggest that ALA augmented folate functionalized NE are able to overcome the challenges of developing safe and effective delivery system with enhanced potential for mammary gland carcinoma therapy.

Prognostic factors in MNU and DMBA-induced mammary tumors in female rats

Chemically-induced mammary tumors in rats by the carcinogens 1-methyl-1-nitrosourea- (MNU) and 7,12-dimethylbenz[a]anthracene (DMBA) are the most widely used models for studies related with human breast cancer. This study aimed to evaluate the immunoexpression of the prognostic factors estrogen receptor α (ERα), progesterone receptor (PR) and Ki-67, in MNU and DMBA-induced rat mammary tumors, in order to know the model that best suits to woman breast cancer. Twenty-eight MNU-induced and 16 DMBA-induced mammary tumors in virgin female Sprague-Dawley rats were analyzed. The expression of the prognostic markers ERα, PR and Ki-67 proliferation index (Ki-67 PI) was assessed by immunohistochemistry. Mitotic activity index (MAI) was also evaluated. More than one histological pattern was identified in each mammary tumor. Carcinomas constituted the lesions most frequently induced by both carcinogens: 33 MNU-induced carcinomas and 23 DMBA-induced carcinomas. All MNU and DMBA-induced mammary carcinomas were ER+/PR+, with a higher expression of ERα when compared with PR. Tumors’ weight, the expression of ERα, PR, Ki-67 PI and MAI were higher in MNU-induced mammary carcinomas when compared with the DMBA-induced ones. Statistically significant differences between groups were observed for ERα, PR and MAI (p<0.05). The higher KI-67 PI and MAI in MNU-induced mammary carcinomas are suggestive of a higher aggressiveness of these carcinomas when compared with the DMBA-induced ones, and consequently a worse response to the therapy and a worse prognosis. In this way, the use of the rat model of MNU-induced mammary tumors is advised in experimental protocols aiming to study more aggressive mammary tumors within the group of double-positive mammary tumors (ER+/PR+).

Taxifolin Inhibits 7,12-Dimethylbenz(a)anthracene-induced Breast Carcinogenesis by Regulating AhR/CYP1A1 Signaling Pathway.

Background:Breast cancer (BC), because of its invasive characteristics, is one of the most common and deadliest cancers among the female population around the world. Research has demonstrated that AhR signaling also plays a vital role in BC initiation and development as well. Therefore, blocking this pathway to natural interferences paves a new channel for the prevention of BC. Several natural compounds such as flavonoids possess the anticancer activities against different cancers.Objective:The present study has been designed to estimate the chemotherapeutic potential of taxifolin (TAX) against 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in Sprague-Dawley rats.Materials and Methods:Initially, the molecular docking analysis of AhR and cytochrome P450s (CYPs) (CYP1A1 and CYP1B1) was performed using MAESTRO tool, in an attempt to rationalize the activity of TAX, based on their CYP1-binding potential. The in vitro CYP1A1 activity was determined by luciferase assay with CYP1A1 substrate luciferin CEE. The in vivo analysis was performed by administrating TAX at 10, 20, 40 mg/kg BW for 28 days intragastrically in DMBA induced (25 mg/animal dose) at 55 days of age Sprague-Dawley (SD) rats. BC initiates after 90 days of tumor induction phase. The molecular mechanism of TAX on Ahr and CYPs was also examined through the mRNA and protein expressions using reverse transcription-quantitative polymerase chain reaction and Western blotting analysis.Results:Furthermore, TAX altered the energy regulation on DMBA-induced BC in SD rats by considerably restoring the cancer-induced modulations in tumor growth. Our results showed that TAX reduced the expressions of CYP1A1 and CYP1B1 in DMBA-induced mammary carcinoma by downregulating the AhR signaling pathway.Conclusion:This study revealed that TAX might be able to act as a chemotherapeutic agent against CYP1A1- and CYP1B1-mediated cancer and the inhibition of the DMBA-induced mammary carcinogenesis in a rat model.Abbreviations used: CYPs: Cytochrome P450s; PAH: polycyclic aromatic hydrocarbons; HRP- Horseradish peroxidase; BSA: Bovine serum albumin; DTTP: Deoxythymidine Triphosphate (nucleotide); RT-qPCR: Real Time quantitative polymerase chain reaction; CADD: Computer Aided Drug Drafting.

Gold nanoparticle–conjugated quercetin inhibits epithelial–mesenchymal transition, angiogenesis and invasiveness via EGFR/VEGFR‐2‐mediated pathway in breast cancer

Epidermal growth factor plays a critical role in breast malignancies by enhancing cell proliferation, invasion, angiogenesis and metastasis. Epithelial-mesenchymal transition (EMT) is a crucial process by which epithelial cells lose polarity and acquire migratory mesenchymal properties. Gold nanoparticles are an efficient drug delivery vehicle for carrying chemotherapeutic agents to target cancer cells and quercetin is an anti-oxidative flavonoid known with potent anti-malignant cell activity. Cell viability was assessed by MTT assay, and protein expression was examined by Western blotting and immunocytochemistry. Cell invasion was monitored using invasion chambers, and cell migration was analysed by scratch wound-healing assay. In vitro and ex vivo angiogenesis studies were performed by capillary-like tube formation assay and chick embryo angiogenesis assay (CEA). 7,12-dimethylbenz(a)anthracene (DMBA) induced mammary carcinoma in Sprague-Dawley rats. We observed a significant reduction in protein expression of vimentin, N-cadherin, Snail, Slug, Twist, MMP-2, MMP-9, p-EGFR, VEGFR-2, p-PI3K, Akt and p-GSK3β, and enhanced E-cadherin protein expression in response to AuNPs-Qu-5 treatment. AuNPs-Qu-5 inhibited migration and invasion of MCF-7 and MDA-MB-231 cells compared to free quercetin. AuNPs-Qu-5-treated HUVECs had reduced cell viability and capillary-like tube formation. In vitro and in vivo angiogenesis assays showed that AuNPs-Qu-5 suppressed tube and new blood vessel formation. Treatment with AuNPs-Qu-5 impeded tumour growth in DMBA-induced mammary carcinoma in SD rats compared to treatment with free quercetin. Our results suggest that AuNPs-Qu-5 inhibited EMT, angiogenesis and metastasis of the breast cancer cells tested by targeting the EGFR/VEGFR-2 signalling pathway.

Erythrocyte Protoporphyrin Fluorescence as a Biomarker to Monitor the Anticancer Effect of Semecarpus Anacardium in DMBA Induced Mammary Carcinoma Rat Model.

Endogenous fluorescence has been proposed as a means of aiding the diagnosis of various malignancies. It has been suggested that erythrocytes may be the carriers of fluorophors that accumulate in cancer tissue and may be useful in the diagnosis and treatment of malignancies. Hence, the present study was designed to explore the spectrofluorimetric analysis of blood components as a marker for the analysis of mammary carcinoma treatment and also to bring about the protective effect of the drug Semecarpus anacardium on oxidative stress mediated damage of erythrocytes. Fluorescence spectra of the blood components were studied and also the level of lipid per oxides and antioxidant enzymes status in erythrocytes were determined in DMBA induced mammary carcinoma rats treated with Semecarpus anacardium Linn nut milk extract. Fluorescence emission spectroscopy of blood components are altered under cancer conditions and the drug effectively ameliorated these alterations in mammary carcinoma induced rats. The drug also effectively reduced the oxidative stress induced erythrocyte damage thereby restoring the erythrocytes antioxidant status. These results suggest that erythrocytes may be the carriers of fluorophors that accumulate in cancer tissue and hence acts as new biomarkers for the diagnosis and treatment.

Free radical quenching effect of Shemamruthaa—a Siddha drug in 7,12-dimethylbenz(a)anthracene-induced experimental breast cancer rats

This study aims to evaluate the modulatory effect of Shemamruthaa (SM), a modified indigenous Siddha formulation, on the hematological indices, membrane-bound enzymes, enzymatic antioxidants free radical levels in cancer rats and also on the histologicl alterations in the mammary tissue. Mammary cancer was induced by intragastric administration of a single dose of 25 mg/kg body weight of 7,12-dimethylbenz(a)anthracene (DMBA), and cancer-induced rats were treated with oral administration of SM at a dosage of 400 mg/kg body weight dissolved in water for 14 days. Hematological indices such as hemoglobin (HB), red blood cells (RBC), white blood cells (WBC), platelets counts and packed cell volume (PCV) were decreased, whereas erythrocyte sedimentation rate (ESR) was increased. Moreover, lipid peroxidation and free radicals were found to be increased, whereas activities of antioxidant enzymes and membrane-bound ATPases were decreased in cancer-bearing animals when compared with control rats. The drug SM also effectively restored morphological alterations in the mammary tissue of cancer-bearing rats. From the results of the present study, the beneficial effect of SM on DMBA-induced mammary carcinoma is evident.

Morin accelerates proliferative inhibition via NF-κB mediated transcriptional regulation of apoptotic events during chemical carcinogen induced mammary cancer in rats

Chemoprevention plays pivotal role in the prevention of human cancers. Morin, a bioflavonoid, has been known for its chemopreventive activities against various cancers and also in recent years, numerous investigations have shown that flavonol containing compounds induce apoptosis in various types of cancers in experimentally induced animal models. Thus the present study was aimed to understand the molecular pathway of inflammation mediated apoptosis regulation is of crucial importance for developing therapeutic agents for the intervention of mammary cancer. In this study, we investigated the protective effects of morin on DMBA-induced mammary carcinoma in Sprague-Dawley rats. Results showed that morin significantly attenuated DMBA-induced inflammation mediated apoptotic cell death. Morin effectively suppressed the down-regulation of bax and up-regulation of bcl-2. Furthermore, morin down-regulated the pro-inflammatory markers such as COX-2, NFkB, TNF-α, IL-2, and IL-1β. We also demonstrated that intrinsic mitochondrial mediated apoptotic events by morin was associated with the release of cytochrome C and apoptotic signaling pathway. Therefore, these results suggest that morin can prevent mammary carcinoma under DMBA-induced conditions by inducing cancer cell death through apoptotic events and thus suggest that it may be clinically evaluated for the chemoprevention of mammary carcinoma.

Immunomodulatory effect of Kalpaamruthaa on 7,12-dimethyl benz(a)anthracene-induced mammary carcinoma studied in rats

Kapaamruthaa is a modified Siddha preparation prepared in our laboratory. It has been proven to have therapeutic effect against arthritis and liver cancer. The present study was carried out to bring about the protective effect of Kalpaamruthaa on experimental mammary carcinoma in rats with special reference to cytokines, carcinoembryonic antigen (CEA), carbohydrate antigen 15–3 (CA 15–3), immunoglobulin levels, and glycoprotein components. Breast cancer was induced in rats by administering 7,12-dimethylbenz(a)anthracene (DMBA) orally (25 mg/rat) as a single dose. After 90 days of induction, Semecarpus anacardium Linn. (200 mg/kg body weight) and Kalpaamruthaa (KA) (300 mg/kg body weight) were administered for 14 days, by gastric intubation. In mammary carcinoma-bearing rats, the levels of interleukin-6, interleukin-8, and tumor necrosis factor-α were significantly increased (p < 0.001) in serum when compared to control rats. The levels of CEA and CA 15–3 were found to be significantly increased (p < 0.001) in mammary carcinoma-bearing rats. The levels of IgG and IgM were significantly decreased (p < 0.001) whereas IgA levels were significantly increased (p < 0.001) in mammary carcinoma-bearing rats. The levels of glycoprotein components namely hexose, hexosamine, and sialic acid were significantly (p < 0.001) increased in the spleen and thymus of the mammary carcinoma-bearing (group II) rats when compared to control rats. Treatment with KA significantly altered the levels of cytokines, CEA, CA 15–3, immunoglobulins, and glycoprotein components to near normal levels when compared to breast cancer-induced rats. The present study suggests the therapeutic effect of KA in DMBA-induced mammary carcinoma in rats.

Human Breast Adenocarcinoma Cytotoxicity and Modulation of 7,12-Dimethylbenz[a]anthracene-Induced Mammary Carcinoma in Balb/c Mice by Acacia catechu (L.f.) Wild Heartwood

The chemopreventive potential of (+)-catechin-rich extract of Acacia catechu (L.f.) Willd. heartwood (AQCE) was evaluated against human breast adenocarcinoma cell line (MCF-7) and 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinoma in Balb/c mice. Cell cytotoxicity was investigated using different colorimetric assays. Apoptosis was observed using diphenylamine assay and fluorescent microscopy. AQCE was further evaluated for antitumor activity against DMBA-induced mammary carcinoma. The levels of tumor markers and oxidative stress were measured. Furthermore, level of transcription factors was measured by enzyme-linked immunosorbent assay. The results showed that administration of AQCE showed a dose-dependent growth inhibition response and DNA fragmentation in MCF-7 cells. Tumor multiplicity was significantly decreased to 42.91% with AQCE when compared with DMBA-treated animals. The levels of tumor markers such as total sialic acid and lipid-associated sialic acid were substantially increased after DMBA treatment. However, AQCE treatment restored tumor markers level. AQCE also significantly reduced elevated levels of nitrite and malondialdehyde in DMBA-treated animals. Additionally, AQCE also increased the activities of antioxidant enzymes, viz., catalase, superoxide dismutase, total thiol, reduced glutathione, protein thiol, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase in the mammary tissue and liver mitochondria of DMBA-administered animals. Significant increase in the protein levels of p53, c-jun, and p65 were observed in DMBA-treated mice, whereas less expression was observed in AQCE-treated animals. Eventually, AQCE also significantly improved body weight and maintained the mammary tissue architecture in normal range. The present data strongly suggest that anticancer potentiality of (+)-catechin-rich AQCE may be attributable to its ability to positively modulate tumor markers as well as the antioxidant system that could decompose the peroxides and, thereby, offer a protection against lipid peroxidation and linked to the expression of transcription factors during DMBA-induced mammary carcinoma.