scholarly journals Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

2021 ◽  
Vol 14 (11) ◽  
pp. 1119
Author(s):  
Azizah M. Malebari ◽  
Shu Wang ◽  
Thomas F. Greene ◽  
Niamh M. O’Boyle ◽  
Darren Fayne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Mitotic Catastrophe ◽  
Phase Cell ◽  
Cancer Drug ◽  
Clinical Activity ◽  
Antimitotic Activity ◽  
Mcf 7

Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound 10n (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound 11n (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC50 values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound 10n demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 10n caused a mitotic catastrophe by targeting tubulin. In addition, compound 10n promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-β-lactams and the amino acid residues of the colchicine binding active site cavity of β-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound 10n, could be promising lead compounds for further clinical anti-cancer drug development.

scholarly journals 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

2019 ◽  
Vol 12 (2) ◽  
pp. 56 ◽  
Author(s):  
Wang ◽  
Malebari ◽  
Greene ◽  
O’Boyle ◽  
Fayne ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Docking Simulation ◽  
Chemotherapeutic Agents ◽  
Mitotic Catastrophe ◽  
Phase Cell ◽  
Tubulin Polymerization ◽  
Mcf 7

Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 M for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

scholarly journals Synthesis and Biological Evaluation of 1-(Diarylmethyl)-1H-1,2,4-triazoles and 1-(Diarylmethyl)-1H-imidazoles as a Novel Class of Anti-Mitotic Agent for Activity in Breast Cancer

2021 ◽  
Vol 14 (2) ◽  
pp. 169
Author(s):  
Gloria Ana ◽  
Patrick M. Kelly ◽  
Azizah M. Malebari ◽  
Sara Noorani ◽  
Seema M. Nathwani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Mitotic Catastrophe ◽  
Phase Cell ◽  
Computational Docking ◽  
Er Positive ◽  
Mcf 7

We report the synthesis and biochemical evaluation of compounds that are designed as hybrids of the microtubule targeting benzophenone phenstatin and the aromatase inhibitor letrozole. A preliminary screening in estrogen receptor (ER)-positive MCF-7 breast cancer cells identified 5-((2H-1,2,3-triazol-1-yl)(3,4,5-trimethoxyphenyl)methyl)-2-methoxyphenol 24 as a potent antiproliferative compound with an IC50 value of 52 nM in MCF-7 breast cancer cells (ER+/PR+) and 74 nM in triple-negative MDA-MB-231 breast cancer cells. The compounds demonstrated significant G2/M phase cell cycle arrest and induction of apoptosis in the MCF-7 cell line, inhibited tubulin polymerisation, and were selective for cancer cells when evaluated in non-tumorigenic MCF-10A breast cells. The immunofluorescence staining of MCF-7 cells confirmed that the compounds targeted tubulin and induced multinucleation, which is a recognised sign of mitotic catastrophe. Computational docking studies of compounds 19e, 21l, and 24 in the colchicine binding site of tubulin indicated potential binding conformations for the compounds. Compounds 19e and 21l were also shown to selectively inhibit aromatase. These compounds are promising candidates for development as antiproliferative, aromatase inhibitory, and microtubule-disrupting agents for breast cancer.

RPF101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the MCF-7 breast cancer cells

2013 ◽  
Vol 266 (3) ◽  
pp. 385-398 ◽  
Author(s):  
Paulo Luiz de-Sá-Júnior ◽  
Kerly Fernanda Mesquita Pasqualoto ◽  
Adilson Kleber Ferreira ◽  
Maurício Temotheo Tavares ◽  
Mariana Celestina Frojuello Damião ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Mitotic Catastrophe ◽  
Microtubule Network ◽  
M Phase ◽  
Mcf 7

scholarly journals ARTEMISININ MODULATING EFFECT ON HUMAN BREAST CANCER CELL LINES WITH DIFFERENT SENSITIVITY TO CYTOSTATICS

2017 ◽  
Vol 39 (1) ◽  
pp. 25-29 ◽  
Author(s):  
V F Chekhun ◽  
N Yu Lukianova ◽  
T Borikun ◽  
T Zadvornyi ◽  
A Mokhir
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Iron Homeostasis ◽  
Chemotherapeutic Agents ◽  
Fold Change ◽  
Breast Cancer Cell Lines ◽  
Cellular Iron ◽  
Mcf 7

Aim: To explore effects of Artemisinin on a series of breast cancer cells with different sensitivity to typical cytotoxic drugs (doxorubicin — Dox; cisplatin — DDP) and to investigate possible artemisinin-induced modification of the mechanisms of drug resistance. Materials and Methods: The study was performed on wild-type breast cancer MCF-7 cell line (MCF-7/S) and its two sublines MCF-7/Dox and MCF-7/DDP resistant to Dox and DDP, respectively. The cells were treated with artemisinin and iron-containing magnetic fluid. The latter was added to modulate iron levels in the cells and explore its role in artemisinin-induced effects. The MTT assay was used to monitor cell viability, whereas changes of expression of selected proteins participating in regulation of cellular iron homeostasis were estimated using immunocytochemical methods. Finally, relative expression levels of miRNA-200b, -320a, and -34a were examined by using qRT-PCR. Results: Artemisinin affects mechanisms of the resistance of breast cancer cells towards both Dox and DDP at sub-toxic doses. The former drug induces changes of expression of iron-regulating proteins via different mechanisms, including epigenetic regulation. Particularly, the disturbances in ferritin heavy chain 1, lactoferrin, hepcidin (decrease) and ferroportin (increase) expression (р ≤ 0.05) were established. The most enhanced increase of miRNA expression under artemisinin influence were found for miRNA-200b in MCF-7/DDP cells (7.1 ± 0.98 fold change), miRNA-320a in MCF-7/Dox cells (2.9 ± 0.45 fold change) and miRNA-34a (1.7 ± 0.15 fold change) in MCF-7/S cells. It was observed that the sensitivity to artemisinin can be influenced by changing iron levels in cells. Conclusions: Artemisinin can modify iron metabolism of breast cancer cells by its cytotoxic effect, but also by inducing changes in expression of iron-regulating proteins and microRNAs (miRNAs), involved in their regulation. This modification affects the mechanisms that are implicated in drug-resistance, that makes artemisinin a perspective modulator of cell sensitivity towards chemotherapeutic agents in cancer treatment.

scholarly journals A Combination of an Antimitotic and a Bromodomain 4 Inhibitor Synergistically Inhibits the Metastatic MDA-MB-231 Breast Cancer Cell Line

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Thandi Mqoco ◽  
André Stander ◽  
Anna-Mart Engelbrecht ◽  
Anna M Joubert
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Breast Cancer Cell Lines ◽  
Mcf 7

Current chemotherapeutic agents have many side effects and are toxic to normal cells, providing impetus to identify agents that can effectively eliminate tumorigenic cells without damaging healthy cells. The aim of this study was to examine whether combining a novel BRD4 inhibitor, ITH-47, with the antimitotic estradiol analogue, ESE-15-ol, would have a synergistic effect on inhibiting the growth of two different breast cancer cell lines in vitro. Our docking and molecular dynamics studies showed that compared to JQ1, ITH-47 showed a similar binding mode with hydrogen bonds forming between the ligand nitrogens of the pyrazole, ASN99, and water of the BRD4 protein. Data from cell growth studies revealed that the GI50 of ITH-47 and ESE-15-ol after 48 hours of exposure was determined to be 15 μM and 70 nM, respectively, in metastatic MDA-MB-231 breast cancer cells. In tumorigenic MCF-7 breast cancer cells, the GI50 of ITH-47 and ESE-15-ol was 75 μM and 60 nM, respectively, after 48 hours of exposure. Furthermore, the combination of 7.5 μM and 14 nM of ITH-47 and ESE-15-ol, respectively, resulted in 50% growth inhibition of MDA-MB-231 cells resulting in a synergistic combination index (CI) of 0.7. Flow cytometry studies revealed that, compared to the control, combination-treated MDA-MB-231 cells had significantly more cells present in the sub-G1 phase and the combination treatment induced apoptosis in the MDA-MB-231 cells. Compared to vehicle-treated cells, the combination-treated cells showed decreased levels of the BRD4, as well as c-Myc protein after 48 hours of exposure. In combination, the selective BRD4 inhibitor, ITH-47, and ESE-15-ol synergistically inhibited the growth of MDA-MB-231 breast cancer cells, but not of the MCF-7 cell line. This study provides evidence that resistance to BRD4 inhibitors may be overcome by combining inhibitors with other compounds, which may have treatment potential for hormone-independent breast cancers.

scholarly journals Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells

2004 ◽  
Vol 11 (5) ◽  
pp. 309-316 ◽  
Author(s):  
Raquel T Lima ◽  
Luís M Martins ◽  
José E Guimarães ◽  
Clara Sambade ◽  
M Helena Vasconcelos
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Human Breast Cancer Cells ◽  
Human Breast ◽  
Mcf 7

scholarly journals A Flavone Constituent from Myoporum bontioides Induces M-Phase Cell Cycle Arrest of MCF-7 Breast Cancer Cells

Molecules ◽  
2017 ◽  
Vol 22 (3) ◽  
pp. 472 ◽  
Author(s):  
Jing-Ru Weng ◽  
Li-Yuan Bai ◽  
Wei-Yu Lin ◽  
Chang-Fang Chiu ◽  
Yu-Chang Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Phase Cell ◽  
Cycle Arrest ◽  
M Phase ◽  
Mcf 7

Recent Trends for Drug Development for the treatment of Adenocarcinoma breast cancer: Thiazole, Triazole, and Thiosemicarbazone Analogues as Efficient Scaffolds

2021 ◽  
Vol 21 ◽  
Author(s):  
Cauê Benito Scarim ◽  
Chung Man Chin
Keyword(s):  
Breast Cancer ◽  
Drug Discovery ◽  
Drug Development ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Medicinal Chemistry ◽  
Chemotherapeutic Agents ◽  
Review Article ◽  
Recent Trends ◽  
Mcf 7

: Thiazoles, triazoles, and thiosemicarbazones function as efficient scaffolds in compounds for the treatment of several illnesses, including cancers. In this review article, we demonstrate the various studies involving these three pharmacophore classes (thiazoles, triazoles, and thiosemicarbazones) in the medicinal chemistry field over the last decade (2011-2021), with a focus on MCF-7 adenocarcinoma breast cancer cells. Our objective is to facilitate drug discovery of novel chemotherapeutic agents by detailing anti-proliferative compounds.

The effect of cholesterol depletion in resistant breast cancer cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11031-e11031
Author(s):  
Virgilio Alexander Villeda ◽  
Indira Benakanakere ◽  
Carl Freter
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Chemotherapeutic Agents ◽  
Multiple Comparison ◽  
Cholesterol Depletion ◽  
Phenol Red ◽  
Cancer Disease ◽  
Mcf 7

e11031 Background: A leading cause of breast cancer chemotherapeutic treatment failure is resistance of cancerous cells towards current anti-estrogen agents. This project investigated the relationship between inhibition of cholesterol synthesis and its effect on resistant breast cancer cells. Methods: MCF-7 cells were maintained in phenol red free media and pretreated with charcoal stripped media for 24 hours prior to the experiments (ensure all exogenous estrogen was taken out). Cells were plated in 96 well plates at 10,000 to 15,000 cells/well. MCF-7 cells were tested for their sensitivity to BIBB515 and whether the proliferation of cells with estrogen could be blocked with BIBB515. The cells were grown for 6 days, on day 7 the cell proliferation was determined by adding MTT and read at 570nM. Results: Estrogen, tamoxifen and anastrazole induced cell proliferation that was controlled by 10µM BIBB515. Inhibiting the cholesterol pathway in combination with tamoxifen induced cell death in MCF-7 cells (cell proliferation of 0.13 ±0.15) compared to tamoxifen alone (0.57±0.041) p<0.001 by one way ANNOVA and multiple comparison by DUNN test. Anastrozole alone induced statistically significant cell proliferation 0.403 ±0.03 compared to combination treatment with BIBB515 (0.05 ± 0.007 p<0.001 by one way ANNOVA and multiple comparison by DUNN test). BIBB515 treatment could also inhibit the estrogen induced cell proliferation in MCF-7 cells. These results indicate that cholesterol inhibitors can be developed to fill a niche area in breast cancer disease management where clinicians would prolong treatment on first-line anti-hormone therapies of tamoxifen and anastrazole for advanced disease patients. Conclusions: Results show that inhibition of cholesterol sensitizes resistant cells to current anti-estrogen chemotherapeutic agents. This finding is significant because it could potentially translate into reduce rates of breast cancer relapse due to regiment failure. Exploiting this mechanism could alter the current treatment regimens, leading to control of the diseases in advanced stages by either inducing tumors to be static or to regress. This strategy may also limit the toxicities involved with chemotherapy.

scholarly journals Deciphering the Molecular Basis of Melatonin Protective Effects on Breast Cells Treated with Doxorubicin: TWIST1 a Transcription Factor Involved in EMT and Metastasis, a Novel Target of Melatonin

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 1011 ◽  
Author(s):  
Javier Menéndez-Menéndez ◽  
Francisco Hermida-Prado ◽  
Rocío Granda-Díaz ◽  
Alicia González ◽  
Juana María García-Pedrero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Intracellular Signaling ◽  
Breast Cancer Cells ◽  
Clock Genes ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Mcf 7

Melatonin mitigates cancer initiation, progression and metastasis through inhibition of both the synthesis of estrogens and the transcriptional activity of the estradiol-ER (Estrogen receptor) complex in the estrogen-dependent breast cancer cell line MCF-7. Moreover, melatonin improves the sensitivity of MCF-7 to chemotherapeutic agents and protects against their side effects. It has been described that melatonin potentiates the anti-proliferative effects of doxorubicin; however, the molecular changes involving gene expression and the activation/inhibition of intracellular signaling pathways remain largely unknown. Here we found that melatonin enhanced the anti-proliferative effect of doxorubicin in MCF-7 but not in MDA-MB-231 cells. Strikingly, doxorubicin treatment induced cell migration and invasion, and melatonin effectively counteracted these effects in MCF-7 but not in estrogen-independent MDA-MB-231 cells. Importantly, we describe for the first time the ability of melatonin to downregulate TWIST1 (Twist-related protein 1) in estrogen-dependent but not in estrogen-independent breast cancer cells. Combined with doxorubicin, melatonin inhibited the activation of p70S6K and modulated the expression of breast cancer, angiogenesis and clock genes. Moreover, melatonin regulates the levels of TWIST1-related microRNAs, such as miR-10a, miR-10b and miR-34a. Since TWIST1 plays a pivotal role in the epithelial to mesenchymal transition, acquisition of metastatic phenotype and angiogenesis, our results suggest that inhibition of TWIST1 by melatonin might be a crucial mechanism of overcoming resistance and improving the oncostatic potential of doxorubicin in estrogen-dependent breast cancer cells.

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