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Molecules (Basel, Switzerland) Aug 2023Thienopyrimidines are structural analogs of quinazolines, and the creation of new 2-alkyl derivatives of ethyl 4-aminothienopyrimidine-6-carboxylates for the study of...
Thienopyrimidines are structural analogs of quinazolines, and the creation of new 2-alkyl derivatives of ethyl 4-aminothienopyrimidine-6-carboxylates for the study of their anti-proliferative properties is of great pharmacological interest. Some 2-alkyl-4-amino-thieno[2,3-]pyrimidines - were synthesized, and their cyto- and phototoxicity against BALB 3T3 cells were established by an in vitro 3T3 NRU test. The obtained results indicate that the tested compounds are not cytotoxic or phototoxic, and that they are appropriate to be studied for their anti-proliferative and anti-tumor properties. The anti-proliferative potential of the compounds was investigated on MCF-7 and MDA-MB-231 cancer cells, as well as a MCF-10A cell line (normal human mammary epithelial cells). The most toxic to MCF-7 was thienopyrimidine with IC 13.42 μg/mL (IC 0.045 μM), followed by compound (IC 28.89 μg/mL or IC 0.11 μM). The thienopyrimidine revealed higher selectivity to MCF-7 and lower activity (IC 367 μg/mL i.e., 1.4 μM) than compound with MCF-10A cells. With respect to MDA-MB-231 cells, ester manifested the highest effect with IC 52.56 μg/mL (IC 0.16 μM), and 2-ethyl derivative revealed IC 62.86 μg/mL (IC 0.24 μM). It was estimated that the effect of the substances on the cell cycle progression was due to cell cycle arrest in the G2 stage for MDA-MB-231, while arrest in G1 was detected for the estrogen (ER)-positive MCF-7 cell line. The tested compound's effects on the change of the zeta potential in the tumorigenic cells utilized in this study were determined. The calculation which we performed of the physicochemical properties and pharmacokinetic parameters influencing the biological activity suggested high intestinal absorption, as well as drug-likeness.
Topics: Animals; Mice; Humans; Estrogens; BALB 3T3 Cells; Carboxylic Acids; Carcinogenesis; Dermatitis, Phototoxic; MCF-7 Cells
PubMed: 37687177
DOI: 10.3390/molecules28176347 -
Naunyn-Schmiedeberg's Archives of... May 2023Breast cancer is the most prevalent diagnosed cancer among women and the main cause of morbidity and mortality. As for breast cancer, MCF-7 cells are an important...
Breast cancer is the most prevalent diagnosed cancer among women and the main cause of morbidity and mortality. As for breast cancer, MCF-7 cells are an important candidate since they are widely utilized in research for estrogen receptor (ER)-positive breast cancer cell assays, and various sub-clones have been identified to reflect different classes of ER-positive tumors with varied levels of nuclear receptor expression. Rhodamines and its derivatives have shown a great interest over the past two decades due to their excellent structural and spectroscopic properties. Rhodamine derivatives have been widely investigated for their mitochondrial targeting and chemotherapeutic properties. Rhodamine derivatives, in particular, have been widely investigated for their therapeutic properties. In this regard, several studies have shown that rhodamine dye derivatives have promising in vitro and in vivo therapeutic efficacy. The present study deals with potential anticancer activity of few synthesized rhodamine derivatives against MCF-7 cell lines.
Topics: Female; Humans; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; MCF-7 Cells; Rhodamines
PubMed: 36595094
DOI: 10.1007/s00210-022-02376-3 -
Toxins Apr 2023Breast cancer is one of the most common cancers in women worldwide. Conventional cancer chemotherapy always has adverse side effects on the patient's healthy tissues....
Breast cancer is one of the most common cancers in women worldwide. Conventional cancer chemotherapy always has adverse side effects on the patient's healthy tissues. Consequently, combining pore-forming toxins with cell-targeting peptides (CTPs) is a promising anticancer strategy for selectively destroying cancer cells. Here, we aim to improve the target specificity of the BinB toxin produced from (Ls) by fusing a luteinizing hormone-releasing hormone (LHRH) peptide to its pore-forming domain (BinB) to target MCF-7 breast cancer cells as opposed to human fibroblast cells (Hs68). The results showed that LHRH-BinB inhibited MCF-7 cell proliferation in a dose-dependent manner while leaving Hs68 cells unaffected. BinB, at any concentration tested, did not affect the proliferation of MCF-7 or Hs68 cells. In addition, the LHRH-BinB toxin caused the efflux of the cytoplasmic enzyme lactate dehydrogenase (LDH), demonstrating the efficacy of the LHRH peptide in directing the BinB toxin to damage the plasma membranes of MCF-7 cancer cells. LHRH-BinB also caused MCF-7 cell apoptosis by activating caspase-8. In addition, LHRH-BinB was predominantly observed on the cell surface of MCF-7 and Hs68 cells, without colocalization with mitochondria. Overall, our findings suggest that LHRH-BinB could be investigated further as a potential cancer therapeutic agent.
Topics: Humans; Female; Breast Neoplasms; Gonadotropin-Releasing Hormone; Toxins, Biological; Cell Membrane; MCF-7 Cells
PubMed: 37104235
DOI: 10.3390/toxins15040297 -
Analytical Chemistry Oct 2022The development of new models that closely mimic the tumor microenvironment (TME) to evaluate the efficacy of anticancer drugs has received great attention. In this...
The development of new models that closely mimic the tumor microenvironment (TME) to evaluate the efficacy of anticancer drugs has received great attention. In this study, a three-dimensional (3D) bioprinted Michigan Cancer Foundation-7 (MCF-7) cancer spheroid-embedded hydrogel model was suggested for integrative determination of the half-maximal inhibitory concentration (IC) values of photosensitizers (PSs). The MCF-7 cell-laden alginate/gelatin hydrogel was printed for the fabrication of tumor spheroids. The hydrogel was used to mimic the extracellular matrix (ECM) surrounding the cancer cells in the TME. The fluorescence intensities corresponding to photodynamic therapy (PDT)-induced death of tumor spheroids probed by the laser showed a random distribution in the hydrogel, regardless of the focus of the laser and the vertical-axis direction in which the laser was passed. These results enabled integrative measurement of all tumor spheroids probed by the laser without needing to separate the tumor spheroids in the hydrogel and measure them individually. When compared with two-dimensional (2D) monolayer cultures, very large IC values of the PSs, chlorin e6 (Ce6) and sulfonated tetraphenyl porphyrin (sTPP), were achieved in MCF-7 spheroid-embedded hydrogels mainly due to the drug resistance of the tumor spheroids. Additionally, the heterogenic PDT response of single MCF-7 cancer cells in a single tumor spheroid was observed through 3D imaging of irregular apoptosis in a single spheroid since single tumor spheroids showed a heterogenic PDT response. Furthermore, the laser-power-dependent IC values of PSs were obtained using the MCF-7 spheroid-embedded hydrogel model.
Topics: Alginates; Antineoplastic Agents; Cell Death; Gelatin; Humans; Hydrogels; MCF-7 Cells; Michigan; Photochemotherapy; Photosensitizing Agents; Porphyrins; Spheroids, Cellular; Tumor Microenvironment
PubMed: 36167500
DOI: 10.1021/acs.analchem.2c03022 -
Monoclonal Antibodies in... Oct 2023The erythropoietin-producing hepatocellular carcinoma (Eph) receptors are the largest receptor tyrosine kinase family. EphB4 is essential for cell adhesion and motility...
The erythropoietin-producing hepatocellular carcinoma (Eph) receptors are the largest receptor tyrosine kinase family. EphB4 is essential for cell adhesion and motility during embryogenesis. Pathologically, EphB4 is overexpressed and contributes to poor prognosis in various tumors. Therefore, specific monoclonal antibodies (mAbs) should be developed to predict the prognosis for multiple tumors with high EphB4 expression, including breast and gastric cancers. This study aimed to develop specific anti-EphB4 mAbs for multiple applications using the Cell-Based Immunization and Screening method. EphB4-overexpressed Chinese hamster ovary (CHO)-K1 (CHO/EphB4) cells were immunized into mice, and we established an anti-EphB4 mAb (clone B4Mab-7), which is applicable for flow cytometry, Western blot, and immunohistochemistry (IHC). B4Mab-7 reacted with endogenous EphB4-positive breast cancer cell line, MCF-7, but did not react with EphB4-knockout MCF-7 (BINDS-52) in flow cytometry. Dissociation constant () values were determined to be 2.9 × 10 M and 1.3 × 10 M by flow cytometric analysis for CHO/EphB4 and MCF-7 cells, respectively. B4Mab-7 detected the EphB4 protein bands from breast cancer cells in Western blot, and stained breast cancer tissues in IHC. Altogether, B4Mab-7 is very useful for detecting EphB4 in various applications.
Topics: Humans; Cricetinae; Animals; Mice; Antibodies, Monoclonal; CHO Cells; Cricetulus; Immunohistochemistry; MCF-7 Cells; Neoplasms
PubMed: 37824755
DOI: 10.1089/mab.2023.0015 -
Oxidative Medicine and Cellular... 2021Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article,...
Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article, we reported the synthesis of a series of new hybrid molecules through merging the structural features of chalcones and pyridothienopyrimidinones. Our results indicated that the synthesis of chalcone-thienopyrimidine derivatives from the corresponding thienopyrimidine and chalcones proceeded in a relatively short reaction time with good yields and high purity. Most of these novel compounds exhibited moderate to robust cytotoxicity against HepG2 and MCF-7 cancer cells similar to that of 5-fluorouracil (5-FU). The results indicated that IC of the two compounds ( and ) showed more potent anticancer activities against HepG2 and MCF-7 than 5-FU. An MTT assay and flow cytometry showed that only and had anticancer activity and antiproliferative activities at the G1 phase against MCF-7 cells, while six compounds (- and ) had cytotoxicity and cell cycle arrest at different phases against HepG2 cells. Their cytotoxicity was achieved through downregulation of Bcl-2 and upregulation of Bax, caspase-3, and caspase-9. Although all tested compounds increased oxidative stress increment of MDA levels and decrement of glutathione reductase (GR) activities compared to control, the , , and in HepG2 and and in MCF-7 achieved the target results. Moreover, there was a positive correlation between cytotoxic efficacy of the compound and apoptosis in both HepG2 ( = 0.531; = 0.001) and MCF-7 ( = 0.219; = 0.349) cell lines. The results of molecular docking analysis of into the binding groove of Bcl-2 revealed relatively moderate binding free energies compared to the selective Bcl-2 inhibitor, DRO. Like venetoclax, compounds showed 2 violations from Lipinski's rule. However, the results of the ADME study also revealed higher drug-likeness scores for compounds than for venetoclax. In conclusion, the tested newly synthesized chalcone-pyridothienopyrimidinone derivatives showed promising antiproliferative and apoptotic effects. Mechanistically, the compounds increased ROS production with concomitant cell cycle arrest and apoptosis. Therefore, regulation of the cell cycle and apoptosis are possible targets for anticancer therapy. The tested compounds could be potent anticancer agents to be tested in future clinical trials after extensive pharmacodynamic, pharmacokinetic, and toxicity profile investigations.
Topics: Apoptosis; Cell Line, Tumor; Chalcones; Hep G2 Cells; Humans; MCF-7 Cells; Molecular Docking Simulation; Molecular Structure; Pyrimidines
PubMed: 35003514
DOI: 10.1155/2021/4759821 -
Discovery Medicine 2022Glycogen synthase kinase 3 beta (GSK3β) has emerged as a therapeutic target for breast cancer. As inhibitors of GSK-3β, 1,2,4-thiadiazole-3,5-dione (TDZD) family...
Glycogen synthase kinase 3 beta (GSK3β) has emerged as a therapeutic target for breast cancer. As inhibitors of GSK-3β, 1,2,4-thiadiazole-3,5-dione (TDZD) family members have been reported as potential candidates for cancer treatment. In this study, the anticancer effects of ethiadin (ETD-174), one of the chemical synthesis compounds of TDZD, were investigated in MCF-7 human breast cancer cells. MCF-7 cells incubated with different doses of ETD-174 for different time periods. CCK-8 assays were carried out to test the effect of ETD-174 on the proliferation of MCF-7 cells. The occurrence of apoptosis was detected by Hoechst 33258 staining and flow cytometry. ETD-174 on cell migration and colony formation were examined by wound healing experiments and soft agar assays. Relative protein expressions were conducted with immunoblot assay. ETD-174 demonstrated a higher degree of cytotoxicity in MCF-7 cells. Topical morphological changes of apoptotic body formation after ETD-174 treatment were observed. Meanwhile, apoptosis was elicited by ETD-174. Also, ETD-174 could inhibit the migration and clonality of MCF-7 cells. After the treatment with ETD-174, the level of phosphorylation of GSK3β in MCF-7 cells increased significantly, and the enzymatic activity of GSK3β decreased. ETD-174 is likely to have an effective suppressor role in breast cancer, suggesting that pharmacological inhibition of GSK3β as a novel treatment modality for breast cancer should warrant further investigation.
Topics: Humans; Female; MCF-7 Cells; Glycogen Synthase Kinase 3 beta; Breast Neoplasms; Apoptosis
PubMed: 36482736
DOI: No ID Found -
Chemico-biological Interactions Jan 2023In order to discover more effective and less toxic drugs in the field of anti-tumor, the backbone structure of 17β-estradiol was modified, and 11 target compounds were...
In order to discover more effective and less toxic drugs in the field of anti-tumor, the backbone structure of 17β-estradiol was modified, and 11 target compounds were synthesized. Compounds 5 and 10, which exhibited better anti-tumor activity and higher selectivity (more than 10-fold), were chosen for further biological investigation. Flow cytometry results indicated that 5 and 10 could arrest MCF-7 cells in the G2 phase and induce apoptosis. Immunohistochemical analysis revealed that 5 and 10 could bind to the estradiol receptor alpha in MCF-7 cells. Western blotting and real-time PCR assays were performed to detect the effects of compounds on apoptosis-related targets at the protein and gene levels. These results showed that both 5 and 10 could dosed-dependently increase the expression of Apaf-1, Bax, caspase-3,8,9 and reduce the expression levels of the anti-apoptotic factors Bcl-2 and Bcl-xL. Besides, the Human apoptosis array assay demonstrated the expression level of death receptor Trail R2/DR5 was upregulated obviously while the expression of TNF R1, IAPs and Hsp27/60/70 were downregulated. On the whole, 5 induced MCF-7 cell death through the endogenous pathway in mitochondria and the exogenous pathway with death receptor Trail R2/DR5.
Topics: Humans; MCF-7 Cells; Apoptosis; Apoptosis Regulatory Proteins; Blotting, Western; Estradiol; TNF-Related Apoptosis-Inducing Ligand; Cell Line, Tumor
PubMed: 36460128
DOI: 10.1016/j.cbi.2022.110286 -
Anti-cancer Agents in Medicinal... 2022Since the binding of estradiol to its receptor promotes breast cancer cell proliferation (in the ER+ tumours), many molecules targeting this protein have been...
BACKGROUND
Since the binding of estradiol to its receptor promotes breast cancer cell proliferation (in the ER+ tumours), many molecules targeting this protein have been synthesized to counteract the estradiol action. Ferrocene derivatives have proved their efficiency against hormone-dependent breast cancer cells (MCF-7).
OBJECTIVE
In this study, we aimed to find new ferrocene derivatives having pharmacochemistry properties as potential drugs against human breast cancer cells.
METHODS
A series of 29 N-ferrocenylmethylaniline derivatives A0-A28 were synthesised, and their anti-proliferative activity against both hormone-dependent (MCF-7) and independent (MDA-MB 231) human breast cancer cell lines were performed using the MTT test. Molecular docking and drug-likeness prediction were also performed for the five most active derivatives towards MCF-7. A QSAR model was also developed for the perdition of the anti-proliferative activity against MCF-7 cell lines using molecular descriptors and MLR analysis.
RESULTS
All studied derivatives demonstrated better cytotoxicity against MCF-7 compared to the MDA-MB-231 cell lines, and compounds A2, A9, A14, A17 and A27 were the most potent ones but still less active than the standard anticancer drug, crizotinib. The QSAR study revealed good predictive ability, as shown by R2 cv = 0.848.
CONCLUSION
In vitro and in silico results indicated that derivatives A2, A9, A14, A17, and A27 possess the highest anti-proliferative activity; these results can be used to design more potent N-ferrocenylmethylaniline derivatives as anti-proliferative agents.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Estradiol; Female; Humans; MCF-7 Cells; Metallocenes; Molecular Docking Simulation; Molecular Structure
PubMed: 34170810
DOI: 10.2174/1871520621666210624141712 -
International Journal of Molecular... Dec 2020Mitochondrial dysfunction plays a significant role in the metabolic flexibility of cancer cells. This study aimed to investigate the metabolic alterations due to...
UNLABELLED
Mitochondrial dysfunction plays a significant role in the metabolic flexibility of cancer cells. This study aimed to investigate the metabolic alterations due to Coenzyme Q depletion in MCF-7 cells.
METHOD
The Coenzyme Q depletion was induced by competitively inhibiting with 4-nitrobenzoate the coq2 enzyme, which catalyzes one of the final reactions in the biosynthetic pathway of CoQ. The bioenergetic and metabolic characteristics of control and coenzyme Q depleted cells were investigated using polarographic and spectroscopic assays. The effect of CoQ depletion on cell growth was analyzed in different metabolic conditions.
RESULTS
we showed that cancer cells could cope from energetic and oxidative stress due to mitochondrial dysfunction by reshaping their metabolism. In CoQ depleted cells, the glycolysis was upregulated together with increased glucose consumption, overexpression of GLUT1 and GLUT3, as well as activation of pyruvate kinase (PK). Moreover, the lactate secretion rate was reduced, suggesting that the pyruvate flux was redirected, toward anabolic pathways. Finally, we found a different expression pattern in enzymes involved in glutamine metabolism, and TCA cycle in CoQ depleted cells in comparison to controls.
CONCLUSION
This work elucidated the metabolic alterations in CoQ-depleted cells and provided an insightful understanding of cancer metabolism targeting.
Topics: Energy Metabolism; Humans; MCF-7 Cells; Mitochondria; Ubiquinone
PubMed: 33379147
DOI: 10.3390/ijms22010198