scholarly journals Concanavalin-A shows synergistic cytotoxicity with tamoxifen via inducing apoptosis in estrogen receptor-positive breast cancer: In vitro and molecular docking studies

2021 ◽  
Author(s):  
Mohamed Elshal ◽  
Norhan Eid ◽  
Ibrahim El-Sayed ◽  
Wael El-Sayed ◽  
Ahmed Ali Al-Karmalawy
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Molecular Docking ◽  
Concanavalin A ◽  
Combined Treatment ◽  
Con A ◽  
Synergistic Cytotoxicity ◽  
Mcf 7 ◽  
Positive Breast Cancer

Background: Tamoxifen (TAM) is the main treatment of estrogen receptor (ER)-positive breast cancer, however; its adverse effects and development of resistance hinder its use. Concanavalin A (Con A) is a mannose/glucose-binding lectin that has been reported to induce apoptosis in a variety of cell lines. Methods: Therefore, we aimed to elucidate the effects of Con A on TAM-induced cell death in ERα positive cell line (MCF-7) and to identify the potential underlying molecular mechanisms using in silico and in vitro techniques. Results: Our results demonstrated that combined treatment with Con A and TAM reduced the expression of ERα, which showed clear synergistic effects on inhibiting the cell viability of MCF-7 cells. Interestingly, the combined treatment induces G1 phase arrest and reduces cyclin D1 activity while increasing apoptosis and autophagy as indicated by decreasing the expression level of anti-apoptosis gene BCl-2 and increased apoptosis/autophagic gene BNIP3. Molecular docking was conducted to evaluate the binding affinity of Con A towards ERα, and it revealed its potential activity as an ERα antagonist. Our data further indicated that Con A administration increased the drug reduction index of TAM. Conclusion: Overall, our findings suggested that Con A could be used as an adjuvant agent with TAM to improve its effectiveness as an anticancer agent while minimizing its side effects.

scholarly journals Synergistic Cytotoxicity between Elephantopus scaber and Tamoxifen on MCF-7-Derived Multicellular Tumor Spheroid

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Wan Yong Ho ◽  
Sok Sian Liew ◽  
Swee Keong Yeap ◽  
Noorjahan Banu Alitheen
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Tumor Spheroid ◽  
Multicellular Tumor Spheroid ◽  
Synergistic Cytotoxicity ◽  
Estrogen Receptor Positive ◽  
Elephantopus Scaber ◽  
Combinatorial Treatment ◽  
Mcf 7 ◽  
Positive Breast Cancer

Elephantopus scaber Linn, a traditional herb, exhibited anticancer properties, and it was cytotoxic against the monolayer estrogen receptor-positive breast cancer cell line, MCF-7, in the previous study. In order to determine the potential of E. scaber as a complementary medicine for breast cancer, this study aimed to evaluate the synergism between E. scaber and tamoxifen in cytotoxicity using MCF-7 in the form of 3-dimensional multicellular tumor spheroid (MCTS) cultures. MCTS represents a more reliable model for studying drug penetration as compared to monolayer cells due to its greater resemblance to solid tumor. Combination of E. scaber ethanol extract and tamoxifen, which were used in concentrations lower than their respective IC50 values, had successfully induced apoptosis on MCTS in this study. The combinatorial treatment showed >58% increase of lactate dehydrogenase release in cell media, cell cycle arrest at the S phase, and 1.3 fold increase in depolarization of mitochondrial membrane potential. The treated MCTS also experienced DNA fragmentation; this had been quantified by TUNEL-positive assay, which showed >64% increase in DNA damaged cells. Higher externalization of phospatidylserine and distorted and disintegrated spheroids stained by acridine orange/propidium iodide showed that the cell death was mainly due to apoptosis. Further exploration showed that the combinatorial treatment elevated caspases-8 and 9 activities involving both extrinsic and intrinsic pathways of apoptosis. The treatment also upregulated the expression of proapoptotic gene HSP 105 and downregulated the expression of prosurvival genes such as c-Jun, ICAM1, and VEGF. In conclusion, these results suggested that the coupling of E. scaber to low concentration of tamoxifen showed synergism in cytotoxicity and reducing drug resistance in estrogen receptor-positive breast cancer.

scholarly journals Yuanhuatine from Daphne genkwa selectively induces mitochondrial apoptosis in estrogen receptor α-positive breast cancer cells in vitro

Planta Medica ◽  
2019 ◽  
Vol 85 (16) ◽  
pp. 1275-1286 ◽  
Author(s):  
Ying-Ying Zhang ◽  
Xin-Yue Shang ◽  
Xue-Wen Hou ◽  
Ling-Zhi Li ◽  
Wei Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Mitochondrial Dysfunction ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Potential Candidate ◽  
Daphne Genkwa ◽  
Mcf 7 ◽  
Positive Breast Cancer

AbstractBreast cancer is one of the most common cancers diagnosed among women worldwide. Estrogen receptor alpha (ERα) is a transcriptional factor that plays an important role in the development and progression of breast cancer. Yuanhuatine, a natural daphnane-type diterpenoid extracted from Daphne genkwa, was reported to exhibit significant cytotoxicity against breast cancer cells. However, the underlying mechanism is still unclear. In this study, we evaluated the cytotoxicity of yuanhuatine on two breast cancer cell lines that are ERα-positive and -negative. The results show that yuanhuatine inhibits the growth of ERα-positive cells (MCF-7) with much stronger inhibitory activity (IC50 = 0.62 µM) compared with positive control tamoxifen (IC50 = 14.43 µM). However, no obvious cytotoxicity was observed in ERα-negative cells (MDA-MB-231). Subsequent experiment also indicated that yuanhuatine markedly induced mitochondrial dysfunction, leading to apoptosis in MCF-7 cells. Molecular docking studies suggest the potential interactions between yuanhuatine and ERα. Immunofluorescence staining and Western blot analysis indicated that yuanhuatine down-regulated the expression of ERα in MCF-7 cells. MPP, a specific ERα inhibitor, significantly enhanced yuanhuatine-induced mitochondrial dysfunction and apoptosis in MCF-7 cells. On the contrary, the treatment with yuanhuatine causes no apoptosis in MM231 cells. Altogether, in vitro and in silico results suggested that ERα down-regulation was involved in yuanhuatine-induced mitochondrial dysfunction and apoptosis in ERα-positive breast cancer cells. Thus, yuanhuatine could be a potential candidate for treating ERα-positive breast cancer.

scholarly journals Virtual screening of natural compounds as combinatorial agents from indian medicinal plants against estrogen positive breast cancer

2020 ◽  
Vol 3 (10) ◽  
pp. 266-275
Author(s):  
Shaleen Jain ◽  
Dr. Asmita Das
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Virtual Screening ◽  
Medicinal Plants ◽  
Natural Compounds ◽  
Binding Energies ◽  
Common Amino Acid ◽  
Estrogen Receptor Positive ◽  
Positive Breast Cancer

Facing worldwide challenges associated with multifactorial etiology of breast cancer, designing of combinatorial therapies using natural compounds is currently the emergent way of treating several cancers including breast cancer in a synergistic way, which may mitigate several problems associated with multiple receptor targeting. In this research, Estrogen receptor positive breast cancer was taken as prototype and several key receptors associated with this particular disease were targeted by virtual screening of natural compounds found in Indian originated medicinal plants using Computer aided Drug Designing (CADD) strategies. We found the combination of Carpusin, Paulownin Cornigerine, Nororientaline, Oryzalexin B, Romucosine H and Colchicine as effective against six potential receptors i.e. FGFR2, ESR1, PIK3CA, PIK3CB, PIK3CD and AR in Estrogen receptor positive breast cancer with their binding energies in the range of ∆G ≤ -8.0 Kcal/mol as well as significant number of common amino acid binding residues as compared with binding sites of receptors. Thus this research holds significant implications for the designing of combinatorial therapeutic agents against breast cancer which can be further tested in-vitro and in-vivo to prove their synergistic efficiency.

scholarly journals 17β-estradiol-containing liposomes as a novel delivery system for the antisense therapy of ER-positive breast cancer: An in vitro study on the MCF-7 cell line

2014 ◽  
Vol 33 (2) ◽  
pp. 921-929 ◽  
Author(s):  
ZBYNEK HEGER ◽  
JAROMIR GUMULEC ◽  
NATALIA CERNEI ◽  
KATERINA TMEJOVA ◽  
PAVEL KOPEL ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Delivery System ◽  
In Vitro Study ◽  
Antisense Therapy ◽  
Er Positive ◽  
17Β Estradiol ◽  
Mcf 7 ◽  
Positive Breast Cancer

Identification of estrogenically synthesized LRP16 as an ERα coactivator and its role in ERα-positive breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10676-10676
Author(s):  
W. Han ◽  
Y. Zhao ◽  
Z. Wu ◽  
Y. Mu ◽  
L. Yu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Northern Blot ◽  
Breast Cancer Cells ◽  
Tumor Diameter ◽  
Er Positive ◽  
Mcf 7 ◽  
Positive Breast Cancer

10676 Background: Aberrant ERα activity is linked to genesis and malignant progression of breast cancer through direct target gene activation or repression. A complex network of coregulatory proteins is largely believed to determine the transcriptional activity of ERα. LRP16 was identified previously to be an estrogen (E2) responsive gene, but its function involving in conferring estrogen signalling pathway is not clear. Methods: Endogenous LRP16 expression in MCF-7 cells was stably suppressed by retrovirus-mediated small interference RNA (siRNA). The effects of LRP16 expression on E2-stimulated growth and invasive ability of MCF-7 cells were determined in vitro and in vivo assays. The effects of LRP16 expression on ERα transactivation were determined by luciferase assays. The interaction of LRP16 and ERα was examined by GST pull-down and coimmunopricipitation (CoIP) assays. Northern blot and Western blot were used to detect the mRNA and protein levels of ER target genes in LRP16-inhibited MCF-7 cells. The LRP16 expression levels in primary breast cancer were detected by Northern blot. Results: Fristly, LRP16 expression was characterized to be dependent on estrogen activities. Then, LRP16 was identified to be an estrogen-independent ERα cofactor in ER-positive breast cancer cells and demonstrate that LRP16 is an essential coactivator to ERα-mediated transactivation in an estrogen-dependent manner. Suppression of LRP16 expression in ER-positive breast cancer cells specifically inhibits the transcription of ER upregulated genes, results in the increase of E-cadherin expression through ER mediation. In vitro and in vivo data demonstrate that suppression of LRP16 inhibits the ability of estrogen-stimulated proliferation and invasiveness of ER-positive breast cancer cells. The pathological and clinical characteristics of human breast cancer includining ER/PR-positiveness, tumor diameter and the involvement of axillary lymphoid nodes were tightly linked with the LRP16 gene expression level. Conclusions: These results establish a mechanistic link between estrogen receptor status, its coactivator LRP16, and progression of ER-positive breast cancers, and may provide a novel antiestrogenic target for the therapy of ER positive breast cancer. No significant financial relationships to disclose.

Translational cell study exploring the role of estrogen receptor β expression as a predictive and/or prognostic factor in breast cancer patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22185-e22185
Author(s):  
S. Saji ◽  
N. Honma ◽  
M. Hirose ◽  
S. Hayashi ◽  
K. Kuroi
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cell Line ◽  
Cancer Patients ◽  
Triple Negative ◽  
Breast Cancer Patients ◽  
Her 2 ◽  
Mcf 7 ◽  
Cell Study ◽  
Positive Breast Cancer

e22185 Background: We have reported that positive expression of Estrogen receptor β (ERβ) was associated with better prognosis in the early breast cancer patients treated with adjuvant tamoxifen monotherapy (J Clin Oncol. 2008). In addition, this was also true in the ERα-negative/PR-negative/Her-2 negative patients. We explored the biological impact of ERβ in breast cancer cell lines to determine whether these observations were due to its prognostic power or predictive power of response to the therapy. Methods: Since MCF-7 cell was ERβ-negative ERα-positive cell line, we established two stable clones of MCF-7 by introducing ERβ expression vector (β-clone 1, β-clone 2) as the model of ERβ-positive ERα-positive breast cancer. MDA-MB 231 cell was used as ERβ-positive triple-negative cell line. These cells were subjected to proliferation, expression and functional analysis. Results: In western blotting, both β-clone 1 and clone 2 showed decreased expression of PR and Her-2 than parent MCF-7, although there were no differences in ERα expression. Expression of ERβ decreased estradiol (E2) induced proliferation ability and rate of cells in S-phase cycle. PPT (ERα-specific agonist) and DPN (ERβ-specific agonist) did not show any difference in response, and IC 50 for 4 OH-tamoxifen and fulvestrant did not differ among MCF-7, β-clone 1 and clone 2 (0.05–0.1 μM). Whereas, cell death due to deprivation of E2 from 1nM to 1pM was more frequently observed in ERβ-expressing clones than in parent MCF-7 cell. These cell deaths did not involve standard apoptosis pathway with caspase-3/7 activation and PARP cleavage. E2, DPN and PPT did not affect the proliferation of ERβ-positive triple negative MDA-MB 231 cell, and IC 50 for 4-OH tamoxifen was too high (8 μM) to be achieved in clinical pharmacological dose. Conclusions: From our cell study, better prognosis of ERβ-positive breast cancer patient who treated with adjuvant tamoxifen is mainly due to its own favorable biological behavior. However, this prognostic impact may include the favorable response to the treatment, when we use estrogen-deprivation therapy such as aromatase inhibitors (AIs). Additional clinical study in AI users would be required to address this issue. No significant financial relationships to disclose.

Design, Synthesis, In Silico and In Vitro Evaluation of Novel Pyrimidine Derivatives as EGFR Inhibitors

2020 ◽  
Vol 20 ◽  
Author(s):  
Gurubasavaraja S.P. Matada ◽  
Nahid Abbas ◽  
Prasad S. Dhiwar ◽  
Rajdeep Basu ◽  
Giles Devasahayam
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Anticancer Activity ◽  
In Silico ◽  
Docking Studies ◽  
Breast Cancer Cell Lines ◽  
Pyrimidine Derivatives ◽  
Molecular Docking Studies ◽  
Mcf 7

Background: The abnormal signaling from tyrosine kinase causes many types of cancers namely breast cancer, non-small cell lung cancer, and chronic myeloid leukemia. This research reports the in-silico, synthesis, and in-vitro study of novel pyrimidine derivatives as EGFR inhibitors. Objective: The objective of the research study is to discover more promising lead compounds using drug discovery process, in which the rational drug design is achieved by the molecular docking and virtual pharmacokinetic studies. Methods: The molecular docking studies were carried out using discovery studio 3.5-version software. The molecules with good docking and binding energy score were synthesized as well as their structures were confirmed by FT-IR, NMR, Mass and elemental analysis. Subsequently molecules were evaluated for their anticancer activity using MDA-MB-231, MCF-7 and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology. Results: Pyrimidine derivatives displayed anticancer activity. Particularly, compound R8 shows significant cytotoxicity against MDA-MB-231 with an IC50 18.5 ± 0.6 µM. Molecular docking studies proved that the compound R8 has good binding fitting by forming hydrogen bonds with amino acid residues at ATP binding sites of EGFR. Conclusion: Eight pyrimidine derivatives were designed, synthesized and evaluated against breast cancer cell lines. Compound R8 significantly inhibited the growth of MDA-MB-231 and MCF-7. Molecular docking studies reveled that compound R8 has good fitting by forming different Hydrogen bonding interactions with amino acids at ATP binding site of epidermal growth factor receptor target. Compound R8 was a promising lead molecule that showed better results as compared to other compounds in in-vitro studies.

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