A new class of coumate benzimidazole hybrids as BRCA-1 mimetics through unconventional binding mode; Synthesis and preliminary cytotoxicity screening

2019 ◽  
Vol 16 ◽  
Author(s):  
Selvaraj Jubie ◽  
Neetu Yadav ◽  
Shyam Sundar P ◽  
Podila Naresh ◽  
Ashish Wadhwani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor Alpha ◽  
Cancer Susceptibility ◽  
Direct Interaction ◽  
Vitro Assay ◽  
Brca1 Protein ◽  
New Class ◽  
Brca 1 ◽  
Er Alpha

Aims: The present work focus to identify a new class of BRCA-1 mimetics that work differently from conventional anti estrogens. Background: It was found that breast cancer susceptibility protein1 (BRCA1) binds to estrogen receptor alpha (ERα) and inhibits its activity by direct interaction between domains within the amino terminus of BRCA1 and the carboxy terminus of ER alpha. Objective: A novel class of hybrids having coumate and benzimidazolone scaffolds were designed to mimic BRCA1 protein, supressing the tumor activity of breast cancer cell. Method: The in silico molecular docking studies of the designed ligands were performed on BRCA-1 binding cavity of ER alpha. The designed hybrids which have given significant docking scores and having optimum binding interactions with key residues been selected for synthesis and in-vitro assay. Result: The compounds NY1 and NY2 exhibited significant effects on suppressing MDA-MB-231 cells in the concentration of 24 µg/ml and 44 µg/ml respectively. Conclusion: The developed coumate-benzimidazolone hybrids may act as Leads as BRCA-1 mimetics. Other: However,to explore their BRCA-1 mimetics potential, additional experimental data are needed.

scholarly journals Role of estrogen receptor coregulators in endocrine resistant breast cancer

2021 ◽  
pp. 385-400
Author(s):  
Kristin A. Altwegg ◽  
Ratna K. Vadlamudi
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Therapy Resistance ◽  
Vital Role ◽  
In Vivo Studies ◽  
Scaffolding Proteins ◽  
Current State ◽  
Er Alpha

Breast cancer (BC) is the most ubiquitous cancer in women. Approximately 70-80% of BC diagnoses are positive for estrogen receptor (ER) alpha (ERα). The steroid hormone estrogen [17β-estradiol (E2)] plays a vital role both in the initiation and progression of BC. The E2-ERα mediated actions involve genomic signaling and non-genomic signaling. The specificity and magnitude of ERα signaling are mediated by interactions between ERα and several coregulator proteins called coactivators or corepressors. Alterations in the levels of coregulators are common during BC progression and they enhance ligand-dependent and ligand-independent ERα signaling which drives BC growth, progression, and endocrine therapy resistance. Many ERα coregulator proteins function as scaffolding proteins and some have intrinsic or associated enzymatic activities, thus the targeting of coregulators for blocking BC progression is a challenging task. Emerging data from in vitro and in vivo studies suggest that targeting coregulators to inhibit BC progression to therapy resistance is feasible. This review explores the current state of ERα coregulator signaling and the utility of targeting the ERα coregulator axis in treating advanced BC.

Rapid in vitro assay for predicting response to fluorouracil in patients with metastatic breast cancer.

1995 ◽  
Vol 13 (2) ◽  
pp. 419-423 ◽  
Author(s):  
R M Elledge ◽  
G M Clark ◽  
J Hon ◽  
M Thant ◽  
R Belt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Response ◽  
Tumor Cells ◽  
Predictive Value ◽  
Metastatic Breast ◽  
In Vitro Assay ◽  
Vitro Assay ◽  
Biopsy Specimens

PURPOSE To determine if a rapid 3H-uridine uptake assay using breast tumor cells from biopsy specimens could predict clinical response to fluorouracil (5FU) in patients with metastatic breast cancer. PATIENTS AND METHODS A double-blind prospective study was conducted of 60 patients with measurable, metastatic breast cancer who had failed to respond to at least one prior chemotherapy regimen. Patients received 5FU 300 mg/m2/d by continuous infusion and were monitored for response. Tumor cells from biopsy specimens were grown in microwells and exposed for 3 days to 0.1, 1.0, 10.0, and 100.00 micrograms/mL of 5FU on strips coated with drug and extracellular matrix. Cells were pulsed with 3H-uridine overnight. Incorporated radioactivity was compared for wells with and without drug. Results were available 4 days from specimen submission. RESULTS Of 45 eligible patients, 11 (24%) were not assessable in vitro. Nine patients were assessable in vitro, but not clinically. Of the remaining 25 patients, who were assessable both clinically and in vitro, there was one complete response (CR), five partial responses (PRs), five cases of stable disease, and 14 cases of progressive disease, for an objective response rate of 24%. Response in vitro was significantly correlated with clinical response (P = .002). Of six clinical responders, five also responded in vitro, for an assay sensitivity of 83%. Of 19 nonresponders, 17 were nonresponders in vitro, for a specificity of 89%. The positive predictive value of the test was 71% (five of seven), and the negative predictive value was 94% (17 of 18). CONCLUSION Results of an in vitro assay were significantly correlated with clinical response in patients with metastatic breast cancer treated with continuous infusion 5FU.

Differential protein kinase activity in ER-positive and ER-negative breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22142-e22142
Author(s):  
R. Ruijtenbeek ◽  
A. Umar ◽  
L. van Houten ◽  
R. Hilhorst ◽  
J. A. Foekens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Breast Tumors ◽  
Protein Kinase Activity ◽  
Vitro Assay ◽  
Peptide Substrates ◽  
Peptide Microarrays ◽  
Er Positive

e22142 Background: Specific protein tyrosine kinases (PTKs) promote cancer progression and are potential drug targets. The presence of the estrogen receptor (ER) is an important criterion in deciding on treatment of patients with breast cancer. Since PTKs can affect the tumors' receptor function, we investigated in our first proof-of-principle study whether it is possible to discriminate ER-positive (ER+) from ER-negative (ER-) tumors based on PTK activity using microarrays containing many PTK peptide substrates. Methods: Cryosections of 12 ER+ and 12 ER- breast tumors were lysed in the presence of appropriate protease and phosphatase inhibitors. The protein kinase activity in the lysates was monitored in vitro using PamChip peptide microarrays, which comprise of 253 PTK peptide substrates derived from known human phosphorylation sites. Peptide phosphorylation through active kinases can be monitored in samples in real time, using a fluorescently labeled phospho-tyrosine specific antibody. Results: Phosphorylation activity profiles were determined in quadruplicate using multiple independent sample preparations. Using ANOVA analysis, out of 253 peptides, several peptides with a different phosphorylation signal in ER+ and ER- samples were found: 22 with p < 0.02 including VEGFR1, 2 and 3 and ADAM9. Multivariate unsupervised analysis using Principle Component Analysis showed a clustering of ER+ samples vs. ER- samples. Predictive analysis was performed using Partial-Least Squares Discriminant Analysis without explicit feature selection. The prediction error obtained from within experiment cross validation was typically in the range 10–20%. The error rate for between experiment prediction was 20%. An average predictive profile was constructed in which peptides with a relatively large weight were included, e.g. ADAM9 and BCAR1. Conclusions: Using PamChip peptide microarrays we have shown that differences in protein kinase activity exist between ER+ and ER- breast tumors. Our in vitro assay is a promising tool to investigate the interplay between kinase and nuclear receptor mediated signaling, with potential relevance to patient selection for targeted therapies. No significant financial relationships to disclose.

Do BRCA 1 mutations affect selected molecular variables in women with breast and ovarian cancer carrying cerebral metastases?

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13017-e13017
Author(s):  
Janina Markowska ◽  
Anna Markowska ◽  
Monika Szarszewska ◽  
Stefan Sajdak ◽  
Pawel Knapp ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cerebral Metastases ◽  
High Expression ◽  
Metastasis Suppressor ◽  
Brca1 Protein ◽  
Cancer Group ◽  
Brca 1 ◽  
The Status

e13017 Background: Cerebral metastases develop in 10-30% of patients with breast cancer and in around 3.3 to 4% of patients with ovarian cancer. The present study evaluates the expression of ER alpha and beta receptors, PR, HER2 and markers associated with metastases: stromal cell-derived factor-1 (SDF1) and its receptor CXCR4, breast cancer metastasis suppressor (BRMS1), astrocyte elevated gene (AEG-1), depending on the status of BRCA1 protein in cancerous cells of the patients (somatic mutation). Methods: The material originated from 30 women with breast cancer and 22 patients with ovarian cancer in whom cerebral metastases were detected. The studies were conducted on paraffin block sections, the markers were detected using immunocytochemistry, employing specific antibodies. Results: In the breast cancer group, BRCA 1 protein expression was detected in 11 patients, absence of the protein in 19. No significant differences were disclosed in the grade of ER, PR, HER2, SDF1, CXCR4, BRMS1 or AG-1 expression which would be dependent on the status of BRCA1. Expression of the proteins failed to correlate with patients' age, clinical advancement at diagnosis, presence of metastases to lymph nodes. Patients with no PR expression significantly more frequently manifested high expression of CXCR4 (p = 0.0436). The ovarian cancer group included 7 patients with expression of BRCA1 protein, absence of such expression was recorded in 15 patients. No statistically significant differences were disclosed in the expression of the studied factors which would be related to the status of BRCA1 in cancer cells. Also, no differences were detected in the expression of the studied factors which would depend on the patient’s age, primary advancement of the disease or histological type of the cancer. Conclusions: Among numerous molecular factors examined in women with breast or ovarian cancer no statistically significant differences were detected which would depend on BRCA1 protein status in cancer cells. The absence of PR expression in women with breast cancer was associated with high expression of CXCR4, which might indicate that PR-negative women with breast cancer exhibit higher metastatic potential.

scholarly journals A Direct Interaction of Axonin-1 with Ngcam-Related Cell Adhesion Molecule (Nrcam) Results in Guidance, but Not Growth of Commissural Axons

2000 ◽  
Vol 149 (4) ◽  
pp. 951-968 ◽  
Author(s):  
Dora Fitzli ◽  
Esther T. Stoeckli ◽  
Stefan Kunz ◽  
Kingsley Siribour ◽  
Christoph Rader ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Direct Interaction ◽  
Longitudinal Axis ◽  
Vitro Assay ◽  
Commissural Axons ◽  
Related Cell

An interaction of growth cone axonin-1 with the floor-plate NgCAM-related cell adhesion molecule (NrCAM) was shown to play a crucial role in commissural axon guidance across the midline of the spinal cord. We now provide evidence that axonin-1 mediates a guidance signal without promoting axon elongation. In an in vitro assay, commissural axons grew preferentially on stripes coated with a mixture of NrCAM and NgCAM. This preference was abolished in the presence of anti–axonin-1 antibodies without a decrease in neurite length. Consistent with these findings, commissural axons in vivo only fail to extend along the longitudinal axis when both NrCAM and NgCAM interactions, but not when axonin-1 and NrCAM or axonin-1 and NgCAM interactions, are perturbed. Thus, we conclude that axonin-1 is involved in guidance of commissural axons without promoting their growth.

scholarly journals Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2

2021 ◽  
Vol 14 (8) ◽  
pp. 791
Author(s):  
Irving Balbuena-Rebolledo ◽  
Itzia Irene Padilla-Martínez ◽  
Martha Cecilia Rosales-Hernández ◽  
Martiniano Bello
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Md Simulations ◽  
New Drugs ◽  
Breast Cancer Cell Lines ◽  
Vitro Assay ◽  
Growth Inhibitory ◽  
Growth Inhibitory Activity ◽  
Potential Inhibitors

Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR.

scholarly journals Computer-Aided Drug Repurposing: A Cyclooxygenase-2 Inhibitor Celecoxib as a Ligand for Estrogen Receptor Alpha

2015 ◽  
Vol 15 (3) ◽  
pp. 274-280 ◽  
Author(s):  
Enade Perdana Istyastono ◽  
Florentinus Dika Octa Riswanto ◽  
Sri Hartati Yuliani
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
In Silico ◽  
Estrogen Receptor Alpha ◽  
Cyclooxygenase 2 ◽  
Cytotoxic Activities ◽  
In Vitro Test ◽  
Receptor Alpha ◽  
Vitro Test

A cyclooxygenase-2 (COX-2) inhibitor celecoxib has been previously reported to have cytotoxic activities towards gastric, prostate, ovarian, colon and breast cancer cell lines. This article reports that the cytotoxic activities of celecoxib could be resulted from its activity as a potent ligand for estrogen receptor alpha (ERα). Aided by molecular docking simulations, an in silico test to examine whether celecoxib is a ligand for estrogen receptor alpha (ERα) was performed followed by in vitro test employing cytotoxic assay using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) method. The compound was extracted from Celebrex®. Measured by using UV spectrophotometric method at 255.5 nm, it was identified that the content of celecoxib was 102.15 mg/271.48 mg capsule content. The in silico test indicated that celecoxib is a potent ligand for ERα. This finding was confirmed experimentally by an in vitro test that celecoxib has a comparable activity as an ERα ligand to tamoxifen, a drug of choice for breast cancer treatment.

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