Diosgenin Nanoparticles Competes Plain Diosgenin on Reviving Biochemical and Histopathological Alterations in DMBA Induced Rat Mammary Carcinoma via Modulating the AhR-Nrf-2 Signaling Cascades

Background: Diosgenin, a steroidal saponin spotted as a primary ingredient in many traditional Chinese medicines, has sparked the attention of researchers owing to its multi-targeted cytotoxicity towards a multitude of cancers. Regrettably, its true potential was bounded by its impoverished physicochemical properties. In order to fully exploit its ability, we plan to fabricate diosgenin into nanoparticle by encapsulating with biodegradable polymer chitosan. Aim: The current research intends to uncover the therapeutic potency of diosgenin encapsulated chitosan nanoparticles (DG@CS-NP) on 7,12dimethylbenz(a)anthracene (DMBA) induced rat mammary carcinoma by optimizing biochemical and histopathological modifications via attenuating Aryl hydrocarbon receptor (AhR) - nuclear factor erythroid-derived 2-related factors (Nrf-2) signaling. Methodology: Breast cancer was induced with a single dose of DMBA (25 mg/kg b.wt). Orally supplied DG 10mg/kg b.wt. and DG@CS-NP 5 mg/kg b.wt to DMBA-induced tumor-bearing rats shortly after tumor onset. After the experimental period, biochemical and histopathological studies were performed using mammary tissue sections. Furthermore, architectural immunohistochemistry was used to reveal the expression of AhR and Nrf-2 in experimental rats. Additionally, diosgenin interactions with these proteins were also evidently confirmed by molecular docking analysis. Result: We noticed that there is an elevated level of lipid peroxidative marker, phase-I detoxification enzymes, total cholesterol (TC), phospholipids (PL), triglycerides (TG), and free fatty acids (FFA) with boosted AhR expressions as well as diminished levels of enzymatic and non-enzymatic antioxidants and Phase – II detoxification enzymes with downtrodden Nrf-2 expressions in the mammary tissues of DMBA-induced rats. On the other contrary, oral dosing of DG@CS-NP 5 mg/kg b.wt, dramatically reverted them to near-normal tiers. Interestingly, molecular docking analyses also corroborate these insights by highlighting diosgenin's significant interactions with AhR and Nrf-2 targets. Conclusion: As an outcome of our observations, we conclude that nano-encapsulation of diosgenin is a potent targeted therapeutic candidate posing a massive impact on breast cancer than plain diosgenin.

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Collagen molecular phenotypic switch between non-neoplastic and neoplastic canine mammary tissues

Scientific Reports ◽

10.1038/s41598-021-87380-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Masahiko Terajima ◽

Yuki Taga ◽

Becky K. Brisson ◽

Amy C. Durham ◽

Kotaro Sato ◽

...

Keyword(s):

Breast Cancer ◽

Mammary Gland ◽

Mammary Carcinoma ◽

Cancer Biology ◽

Type I Collagen ◽

Critical Role ◽

Premature Death ◽

Mammary Tissue ◽

Type I ◽

Cross Links

AbstractIn spite of major advances over the past several decades in diagnosis and treatment, breast cancer remains a global cause of morbidity and premature death for both human and veterinary patients. Due to multiple shared clinicopathological features, dogs provide an excellent model of human breast cancer, thus, a comparative oncology approach may advance our understanding of breast cancer biology and improve patient outcomes. Despite an increasing awareness of the critical role of fibrillar collagens in breast cancer biology, tumor-permissive collagen features are still ill-defined. Here, we characterize the molecular and morphological phenotypes of type I collagen in canine mammary gland tumors. Canine mammary carcinoma samples contained longer collagen fibers as well as a greater population of wider fibers compared to non-neoplastic and adenoma samples. Furthermore, the total number of collagen cross-links enriched in the stable hydroxylysine-aldehyde derived cross-links was significantly increased in neoplastic mammary gland samples compared to non-neoplastic mammary gland tissue. The mass spectrometric analyses of type I collagen revealed that in malignant mammary tumor samples, lysine residues, in particular those in the telopeptides, were markedly over-hydroxylated in comparison to non-neoplastic mammary tissue. The extent of glycosylation of hydroxylysine residues was comparable among the groups. Consistent with these data, expression levels of genes encoding lysyl hydroxylase 2 (LH2) and its molecular chaperone FK506-binding protein 65 were both significantly increased in neoplastic samples. These alterations likely lead to an increase in the LH2-mediated stable collagen cross-links in mammary carcinoma that may promote tumor cell metastasis in these patients.

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Quantification of the collagen fibers of healthy and neoplastic mammary tissue in cats by the Picrossirius Red histochemical method

Brazilian Journal of Veterinary Pathology ◽

10.24070/bjvp.1983-0246.v14i1p18-23 ◽

2021 ◽

Vol 14 (1) ◽

pp. 18-23

Author(s):

Mariana Jorge ◽

◽

Ana Patrocínio ◽

Alessandre Hataka ◽

Julio Sequeira

Keyword(s):

Breast Cancer ◽

Mammary Carcinoma ◽

Collagen Fibers ◽

Histochemical Method ◽

Mammary Tissue ◽

Control Group ◽

Cancer Tissue ◽

Mean Values ◽

Multiple Comparison Test ◽

Feline Mammary Carcinoma

Although feline mammary carcinoma is not the most prevalent among the species, its aggressive behavior represents a low life expectancy, compared with most undifferentiated types of breast cancer. Tissue stiffness induced by the accumulation of collagen fibers is related to a risk factor for carcinogenesis in healthy women and aggressiveness in those with breast cancer, which can also occur in cats. The objective of this work is to identify the relationship between stromal collagen density and aggressiveness of mammary carcinoma in cats, according to the peripheral and central tissue distribution by the Picrossirius Red histochemical method. Image.J® and MatLab® software were used for digital image processing. The mean values of kurtosis and entropy attributes were grouped into a control group, and low and high-grade carcinoma groups, analyzed with one-way ANOVA and Bonferroni’s multiple comparison test (p <0.01). Interpretation of stromal dynamics is important to evaluate both central and peripheral locations. According to entropy, there was a significant increase in the peripheral density in the carcinoma groups in relation to the control group, which can be justified by blood support. The same can be said of the central region, with a significant gain in collagen fibers from the tumors, indicated by kurtosis. The results suggest the presence of increases in stromal density in mammary carcinomas of cats, regardless of their graduation, and occurring in both regions.

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CHEMOTHERAPEUTIC EFFICACY OF TRIDHAM AND 1,2,3,4,6-PENTA-O-GALLOYL-β-DGLUCOSE ON ANTIOXIDANTS STATUS AND TUMOR MARKERS IN EXPERIMENTAL MAMMARY CARCINOMA IN SPRAGUE-DAWLEY RATS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2016.v9i5.13247 ◽

2016 ◽

Vol 9 (5) ◽

pp. 202 ◽

Cited By ~ 1

Author(s):

Karthick Dharmalingam ◽

Stalin Ramakrishnan ◽

Sachidanandam Panchanatham ◽

Shanthi Palanivelu*

Keyword(s):

Breast Cancer ◽

Tumor Markers ◽

Mammary Carcinoma ◽

Lipid Peroxides ◽

Experimental Period ◽

Control Group ◽

Sprague Dawley ◽

Standard Drug ◽

Group I ◽

Sprague Dawley Rats

ABSTRACTObjective: To study the restorative effect of Tridham (TD) and 1,2,3,4,6-penta-o-galloyl-β-D-glucose (PGG) on 7,12-dimethyl benz(a)anthracene(DMBA)-induced mammary carcinoma in female Sprague-Dawley rats.Methods: Rats were divided into seven groups of six animals each. Group I rats served as control. Group II - mammary carcinoma was inducedby DMBA. Group III and Group IV were induced with DMBA and subsequently treated with TD and PGG, respectively, for 48 days. Group V wastreated with DMBA and subsequently with a standard drug, cyclophosphamide (CYC). Group VI and Group VII were given TD and PGG alone,respectively, for 48 days. After the experimental period, the levels of lipid peroxides (LPO), activities of enzymic and non-enzymic antioxidantssuch as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, reduced glutathione, vitamin C, and vitamin E wereevaluated in the breast tissue of control and experimental rats. Levels of LPO, marker enzymes such as 5’-nucleotidase and lactate dehydrogenase,were also evaluated.Results: The levels of enzymic and non-enzymic antioxidants were decreased in DMBA-induced rats when compared to control rats. The levels oftumor markers were increased in DMBA-induced rats when compared to control rats. These parameters were restored to near normal levels ontreatment with TD and PGG.Conclusions: The results suggest that TD and PGG have a cytoprotective role in DMBA-induced breast cancer-bearing rats. The effect of TD and PGGwas found to be more pronounced than CYC, a standard drug.Keywords: Breast cancer, Tridham, Penta galloyl glucose, Antioxidants, Tumor markers, Sprague-Dawley rats.

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Structure Guided Molecular Docking Assisted Alignment Dependent 3DQSAR Study on Steroidal Aromatase Inhibitors (SAIs) as Anti-breast Cancer Agents

Letters in Drug Design & Discovery ◽

10.2174/1570180815666181010101024 ◽

2019 ◽

Vol 16 (7) ◽

pp. 808-817 ◽

Cited By ~ 3

Author(s):

Laxmi Banjare ◽

Sant Kumar Verma ◽

Akhlesh Kumar Jain ◽

Suresh Thareja

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Aromatase Inhibitors ◽

Direct Synthesis ◽

3D Qsar ◽

Chemotherapeutic Agents ◽

Modeling Tools ◽

Data Set ◽

Wide Range ◽

Steroidal Aromatase Inhibitors

Background: In spite of the availability of various treatment approaches including surgery, radiotherapy, and hormonal therapy, the steroidal aromatase inhibitors (SAIs) play a significant role as chemotherapeutic agents for the treatment of estrogen-dependent breast cancer with the benefit of reduced risk of recurrence. However, due to greater toxicity and side effects associated with currently available anti-breast cancer agents, there is emergent requirement to develop target-specific AIs with safer anti-breast cancer profile. Methods: It is challenging task to design target-specific and less toxic SAIs, though the molecular modeling tools viz. molecular docking simulations and QSAR have been continuing for more than two decades for the fast and efficient designing of novel, selective, potent and safe molecules against various biological targets to fight the number of dreaded diseases/disorders. In order to design novel and selective SAIs, structure guided molecular docking assisted alignment dependent 3D-QSAR studies was performed on a data set comprises of 22 molecules bearing steroidal scaffold with wide range of aromatase inhibitory activity. Results: 3D-QSAR model developed using molecular weighted (MW) extent alignment approach showed good statistical quality and predictive ability when compared to model developed using moments of inertia (MI) alignment approach. Conclusion: The explored binding interactions and generated pharmacophoric features (steric and electrostatic) of steroidal molecules could be exploited for further design, direct synthesis and development of new potential safer SAIs, that can be effective to reduce the mortality and morbidity associated with breast cancer.

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Synthesis, In-vitro and Docking Analysis of C-3 substituted Coumarin Analogues as Anticancer Agents C-3 Substituted Coumarins as Anticancer Agents

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200120114641 ◽

2020 ◽

Vol 16 ◽

Author(s):

Anuradha Thakur ◽

Kamalpreet Kaur ◽

Praveen Sharma ◽

Ramit Singla ◽

Sandeep Singh ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Anticancer Agents ◽

Proliferative Activity ◽

Binding Interaction ◽

Diverse Range ◽

Mcf 7 ◽

Substituted Coumarins

Background: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effect along with multi-drug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity. Objectives: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-α target protein by molecular docking. Method: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software. Results: Among the synthesized analogues 12 and 13 show good antiproliferative activity with IC50 values 1and 1.3 µM respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit dock score of -4.10 kcal/mol and -4.38 kcal/mol respectively. Conclusion: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future.

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Design, Synthesis, In Vitro Anti-cancer Activity, ADMET Profile and Molecular Docking of Novel Triazolo[3,4-a]phthalazine Derivatives Targeting VEGFR-2 Enzyme

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180412123833 ◽

2018 ◽

Vol 18 (8) ◽

pp. 1184-1196 ◽

Cited By ~ 13

Author(s):

Abdel-Ghany A. El-Helby ◽

Helmy Sakr ◽

Rezk R.A. Ayyad ◽

Khaled El-Adl ◽

Mamdouh M. Ali ◽

...

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Cell Lines ◽

Colon Adenocarcinoma ◽

Human Colon ◽

Kinase Assay ◽

Anticancer Activities ◽

In Silico Admet ◽

Human Colon Adenocarcinoma ◽

Mcf 7

Background: Extensive studies were reported in the synthesis of several phthalazine derivatives as promising anticancer agents as potent VEGFR-2 inhibitors. Vatalanib (PTK787) was the first anilinophthalazine published derivative as a potent inhibitor of VEGFR. The discovery of vatalanib as a clinical candidate led to the design and synthesis of different anilinophthalazine derivatives as potent inhibitors for VEGFR-2. The objective of present research work is the synthesis of new agents with the same essential pharmacophoric features of the reported and clinically used VEGFR-2 inhibitors (e.g vatalanib and sorafenib). The main core of our molecular design rationale comprised bioisosteric modification strategies of VEGFR-2 inhibitors at four different positions. </P><P> Material and Methods: A correlation between structure and biological activity of our designed phthalazines was established using molecular docking and VEGFR-2 kinase assay. Results and Discussion: In view of their expected anticancer activity, novel triazolo[3,4-a]phthalazine derivatives 5-6a-o and 3-substituted-bis([1,2,4]triazolo)[3,4-a:4',3'-c]phthalazines 9a-b were designed, synthesized and evaluated for their anti-proliferative activity against two human tumor cell lines HCT-116 human colon adenocarcinoma and MCF-7 breast cancer. It was found that, compound 6o the most potent derivative against both HCT116 and MCF-7 cancer cell lines. Compounds 6o, 6m, 6d and 9b showed the highest anticancer activities against HCT116 human colon adenocarcinoma with IC50 of 7±0.06, 13±0.11, 15±0.14 and 23±0.22 µM respectively while compounds 6o, 6d, 6a and 6n showed the highest anticancer activities against MCF-7 breast cancer with IC50 of 16.98±0.15, 18.2±0.17, 57.54±0.53 and 66.45±0.67 µM respectively. Sorafenib as a highly potent VEGFR-2 inhibitor was used as a reference drug with IC50 of 5.47±0.3 and 7.26±0.3 µM respectively. Nine compounds were further evaluated for their VEGFR-2 inhibitory activity. Compounds 6o, 6m, 6d and 9b emerged as the most active counterparts against VEGFR-2 with IC50 values of 0.1±0.01, 0.15±0.02, 0.28±0.03 and 0.38±0.04 µM, respectively comparable to that of sorafenib (IC50 = 0.1±0.02) µM. Furthermore, molecular docking studies were carried out for all synthesized compounds to investigate their binding pattern and predict their binding affinities towards VEGFR-2 active site. In silico ADMET studies were calculated for the tested compounds. Most of our designed compounds exhibited good ADMET profile. Conclusion: The obtained results showed that, the most active compounds could be useful as a template for future design, optimization, adaptation and investigation to produce more potent and selective VEGFR-2 inhibitors with higher anticancer analogs.

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Toronto Workshop on Late Recurrence in Estrogen Receptor–Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations

JNCI Cancer Spectrum ◽

10.1093/jncics/pkz050 ◽

2019 ◽

Vol 3 (4) ◽

Cited By ~ 2

Author(s):

Ryan J O Dowling ◽

Kevin Kalinsky ◽

Daniel F Hayes ◽

Francois-Clement Bidard ◽

David W Cescon ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

International Workshop ◽

Recurrence Risk ◽

Late Recurrence ◽

Current Understanding ◽

Breast Cancer Patients ◽

Related Factors ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

Abstract Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor–positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor–positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.

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Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells

Scientific Reports ◽

10.1038/s41598-021-88816-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

YoungJun Ju ◽

Yaacov Ben-David ◽

Daniela Rotin ◽

Eldad Zacksenhaus

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Translation Initiation ◽

Triple Negative ◽

Elongation Factor ◽

Protein Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Related Factors ◽

Metabolic Conditions

AbstractThe eukaryotic elongation factor-2 kinase, eEF2K, which restricts protein translation elongation, has been identified as a potential therapeutic target for diverse types of malignancies including triple negative breast cancer (TNBC). However, the contexts in which eEF2K inhibition is essential in TNBC and its consequences on the proteome are largely unknown. Here we show that genetic or pharmacological inhibition of eEF2K cooperated with glutamine (Gln) starvation, and synergized with glutaminase (GLS1) inhibitors to suppress growth of diverse TNBC cell lines. eEF2K inhibition also synergized with depletion of eukaryotic translation initiation factor 4E-binding protein 1 (eIF4EBP1; 4EBP1), a suppressor of eukaryotic protein translation initiation factor 4E (eIF4E), to induce c-MYC and Cyclin D1 expression, yet attenuate growth of TNBC cells. Proteomic analysis revealed that whereas eEF2K depletion alone uniquely induced Cyclin Dependent Kinase 1 (CDK1) and 6 (CDK6), combined depletion of eEF2K and 4EBP1 resulted in overlapping effects on the proteome, with the highest impact on the ‘Collagen containing extracellular matrix’ pathway (e.g. COL1A1), as well as the amino-acid transporter, SLC7A5/LAT1, suggesting a regulatory loop via mTORC1. In addition, combined depletion of eEF2K and 4EBP1 indirectly reduced the levels of IFN-dependent innate immune response-related factors. Thus, eEF2K inhibition triggers cell cycle arrest/death under unfavourable metabolic conditions such as Gln-starvation/GLS1 inhibition or 4EBP1 depletion, uncovering new therapeutic avenues for TNBC and underscoring a pressing need for clinically relevant eEF2K inhibitors.

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QSAR, molecular docking studies, ligand-based design and pharmacokinetic analysis on Maternal Embryonic Leucine Zipper Kinase (MELK) inhibitors as potential anti-triple-negative breast cancer (MDA-MB-231 cell line) drug compounds

Bulletin of the National Research Centre ◽

10.1186/s42269-021-00541-x ◽

2021 ◽

Vol 45 (1) ◽

Author(s):

Hadiza Abdulrahman Lawal ◽

Adamu Uzairu ◽

Sani Uba

Keyword(s):

Breast Cancer ◽

Molecular Docking ◽

Triple Negative Breast Cancer ◽

Leucine Zipper ◽

Triple Negative ◽

Qsar Model ◽

Docking Studies ◽

Model Parameters ◽

Standard Drug ◽

Molecular Docking Studies

Abstract Background Cancer of the breast is known to be among the top spreading diseases on the globe. Triple-negative breast cancer is painstaking the most destructive type of mammary tumor because it spreads faster to other parts of the body, with high chances of early relapse and mortality. This research would aim at utilizing computational methods like quantitative structure–activity relationship (QSAR), performing molecular docking studies and again to further design new effective molecules using the QSAR model parameters and to analyze the pharmacokinetics “drug-likeliness” properties of the new compounds before they could proceed to pre-clinical trials. Results The QSAR model of the derivatives was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments of (R2) = 0.6715, (R2adj) = 0.61920, (Q2) = 0.5460 and (R2pred) of 0.5304, and the model parameters (AATS6i and VR1_Dze) were used in designing new derivative compounds with higher potency. The molecular docking studies between the derivative compounds and Maternal Embryonic Leucine Zipper Kinase (MELK) protein target revealed that ligand 2, 9 and 17 had the highest binding affinities of − 9.3, − 9.3 and − 8.9 kcal/mol which was found to be higher than the standard drug adriamycin with − 7.8 kcal/mol. The pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test and also the Lipinski rule of five. Conclusions The results obtained from the QSAR mathematical model of parthenolide derivatives were used in designing new derivatives compounds that were more effective and potent. The molecular docking result of parthenolide derivatives showed that compounds 2, 9 and 17 had higher docking scores than the standard drug adriamycin. The compounds would serve as the most promising inhibitors (MELK). Furthermore, the pharmacokinetics analysis carried out on the newly designed compounds revealed that all the compounds passed the drug-likeness test (ADME and other physicochemical properties) and they also adhered to the Lipinski rule of five. This gives a great breakthrough in medicine in finding the cure to triple-negative breast cancer (MBA-MD-231 cell line).

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