The anti-oestrogen ICI 182,780, but not tamoxifen, inhibits the growth of MCF-7 breast cancer cells refractory to long-term oestrogen deprivation through down-regulation of oestrogen receptor and IGF signalling

Long-term culture of MCF-7 wild-type (wt) cells in steroid-depleted medium (LTED) results in hypersensitivity to oestradiol (E2) coinciding with elevated levels of ERα and enhanced growth factor signalling. In this study, we aimed to compare the effects of the pure anti-oestrogen ICI 182,780 (ICI) with the competitive anti-oestrogen tamoxifen (TAM) on oestrogen and IGF signalling in these cells. Wt MCF-7 and LTED cells were treated with a log 7 concentration range of E2, TAM or ICI. Effects on cell growth, ERα transactivation, expression of ERα, ERβ and components of the IGF pathway were measured with and without insulin. In the presence of insulin, growth of LTED cells was refractory to TAM but inhibited by ICI and E2. In the absence of insulin, LTED cells showed persistent hypersensitivity to E2, and remained inhibited by ICI but were largely unaffected by TAM. ICI but not TAM inhibited ER-mediated gene transcription and treatment with ICI resulted in a dose-dependent reduction in ERα levels whilst having no effect on ERβ expression. IGF-I receptor and insulin receptor substrate 2 levels were increased in LTED versus the Wt MCF-7 cells, and ICI but not TAM reduced their expression in a dose-dependent fashion. Thus IGF signalling as well as ERα expression and function are enhanced during LTED. While the resultant cells are resistant to TAM, ICI down-regulates ERα, reducing IGF signalling and cell growth. These results support the use of ICI in women with ER-positive breast cancer who have relapsed on an aromatase inhibitor.

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Cytotoxicity Induced by Newly Synthesized Palladium (II) Complexes Lead to the Death of MCF-7 and MDA-MB-435 Cancer Cell Lines

Advanced Pharmaceutical Bulletin ◽

10.34172/apb.2023.017 ◽

2021 ◽

Author(s):

Bruna Alexandre Oliveira da Silva ◽

Isabela Spido Dias ◽

Luís Eduardo Sarto ◽

Elba Pereira de Gois ◽

Claudia Torres ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cell Growth ◽

Cell Lines ◽

Control Group ◽

Cytotoxic Activities ◽

Anticancer Activities ◽

Morphological Alterations ◽

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Purpose: Breast cancer is the most common female malignancy and melanoma is the most lethal type of skin cancer. Traditional therapy for cancer treatment is far from satisfactory due to drug resistance and side effects, thus a search for new medicines is being emphasized. Palladium(II) complexes have been reported as anticancer potential agents. In this work, the anticancer activities and cell death induction of a new series of square-planar palladium(II) complexes were evaluated against MCF-7 and MDA-MB-435 cancer cells. Methods: MCF-7 (breast carcinoma) and MDA-MB-435 (melanoma) cells were cultivated, and treated with ligand and Pd(II) complexes. Cell growth, migration and adhesion inhibition, morphological alterations, cell death induction and, DNA interaction upon treatment were studied. Results: Pd(II) complexes exhibited both short and long-term antiproliferative effects on both cell lines, reducing by 80% cell growth in the SRB assay and abolishing long-term proliferation, estimated by the clonogenic assay. Complexes reduced significantly (p < 0.05) cell migration and adhesion when compared to the control group. Complexes induced morphological alterations in cell lines and significant (p<0.05) cellular shrinkage. Cell death was induced and the complexes were able to interact with DNA, inducing cleavage of double-stranded DNA, which may account for the complexes cytotoxic effects, observed against both MCF-7 and MDA-MB-435 cells. Conclusion: Overall, the complexes exhibited cytotoxic activities and induced cell death. These observations emphasize an anticancer role with a potential therapeutic value for Pd(II) complexes to improve the outcome of patients with breast cancer and melanoma.

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Synergistic cytotoxic effects of tamoxifen and black cohosh on MCF-7 and MDA-MB-231 human breast cancer cells: an in vitro studyThis article is one of a selection of papers published in this special issue (part 2 of 2) on the Safety and Efficacy of Natural Health Products.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y07-111 ◽

2007 ◽

Vol 85 (11) ◽

pp. 1153-1159 ◽

Cited By ~ 16

Author(s):

Mahéra Al-Akoum ◽

Sylvie Dodin ◽

Ali Akoum

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cytotoxic Effect ◽

Black Cohosh ◽

Proliferative Effect ◽

Dose Dependent ◽

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Breast cancer cell cultures were exposed to different concentrations of black cohosh, estradiol (E2), and tamoxifen to examine the effect on cell proliferation; cytotoxicity was assessed by using sulforhodamine B (SRB) dye solution. E2 (10−10–10−8 mol/L) markedly stimulated the proliferation of MCF-7 cells (p < 0.01). Tamoxifen stimulated MCF-7 cell proliferation at 10−6 mol/L and 10−5 mol/L (p < 0.005) but inhibited in a dose-dependent fashion the proliferative effect of E2 (p < 0.001). Black cohosh alone did not show any stimulatory effect, but exhibited a cytotoxic effect, which was significant at 103 μg/mL (p < 0.001). Adding black cohosh at 100–103 μg/mL to E2 at 10−9 mol/L also resulted in a dose-dependent inhibition of E2 proliferative effect. Interestingly, the combination of black cohosh (100–103 μg/mL) with increasing tamoxifen concentrations further inhibited MCF-7 cell growth. On MDA-MB-231 cells, neither E2 nor tamoxifen displayed any detectable effect. However, black cohosh inhibited MDA-MB-231 cell proliferation at 103 μg/mL (p < 0.05), and this inhibitory effect was enhanced by increasing tamoxifen concentrations. This study reveals a cytotoxic effect of black cohosh on both estrogen-sensitive and estrogen-insensitive breast cancer cells and a synergism with tamoxifen for inhibition of cancerous cell growth.

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Effect of Estrogen on Heteronemin-Induced Anti-proliferative Effect in Breast Cancer Cells With Different Estrogen Receptor Status

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.688607 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yu-Chen S. H. Yang ◽

Zi-Lin Li ◽

Tung-Yung Huang ◽

Kuan-Wei Su ◽

Chi-Yu Lin ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Estrogen Receptor ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Breast Cancer Cells ◽

Gene Expressions ◽

Er Positive ◽

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Estrogen (E2) has multiple functions in breast cancers including stimulating cancer growth and interfering with chemotherapeutic efficacy. Heteronemin, a marine sesterterpenoid-type natural product, has cytotoxicity on cancer cells. Breast cancer cell lines, MCF-7 and MDA-MB-231, were used for investigating mechanisms involved in inhibitory effect of E2 on heteronemin-induced anti-proliferation in breast cancer cells with different estrogen receptor (ER) status. Cytotoxicity was detected by cell proliferation assay and flow cytometry, gene expressions were determined by qPCR, mechanisms were investigated by Western blot and Mitochondrial ROS assay. Heteronemin exhibited potent cytotoxic effects against both ER-positive and ER-negative breast cancer cells. E2 stimulated cell growth in ER-positive breast cancer cells. Heteronemin induced anti-proliferation via suppressing activation of ERK1/2 and STAT3. Heteronemin suppressed E2-induced proliferation in both breast cancer cells although some gene expressions and anti-proliferative effects were inhibited in the presence of E2 in MCF-7 and MDA-MB-231 cells with a higher concentration of heteronemin. Heteromenin decreased the Bcl-2/Bax ratio to inhibit proliferation in MDA-MB-231 but not in MCF-7 cells. Both heteronemin and E2 increased mitochondrial reactive oxygen species but combined treatment reversed superoxide dismutase (SOD)s accumulation in MCF-7 cells. Heteronemin caused G0/G1 phase arrest and reduced the percentage of cells in the S phase to suppress cancer cell growth. In conclusion, Heteronemin suppressed both ER-positive and ER-negative breast cancer cell proliferation. Interactions between E2 and heteronemin in signal transduction, gene expressions, and biological activities provide insights into the complex pathways by which anti-proliferation is induced by heteronemin in E2-replete environments.

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Dual Effects of N,N-dimethylformamide on Cell Proliferation and Apoptosis in Breast Cancer

Dose-Response ◽

10.1177/1559325817744450 ◽

2017 ◽

Vol 15 (4) ◽

pp. 155932581774445 ◽

Cited By ~ 4

Author(s):

Jihong Zhang ◽

Daibing Zhou ◽

Lingyun Zhang ◽

Qunbo Lin ◽

Weimin Ren ◽

...

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cell Growth ◽

Inhibitory Effect ◽

High Dose ◽

Dependent Manner ◽

Cyclin E1 ◽

Proliferation And Apoptosis ◽

Dose Dependent ◽

Mcf 7

N,N-dimethylformamide (DMF) has been widely used as an organic solvent in industries. DMF is a potential medication. However, the antitumorigenic role of DMF in breast cancer remains unclear. Here, we examined dose-dependent effects of DMF on proliferation and apoptosis in breast cancer MCF-7 and nontumorous MCF-12A cells. We found that DMF had a growth inhibitory effect in MCF-12A cells in a dose-dependent manner. By contrast, however, DMF had dual effects on cell proliferation and apoptosis in MCF-7 cells. DMF at a high dose (100 mM) significantly inhibited MCF-7 cell growth while at a low dose (1 mM) significantly stimulated MCF-7 cell growth (both P < .05). The inhibitory effect of DMF on cell proliferation was accompanied by the decrease of cyclin D1 and cyclin E1 protein expression, leading to the cell cycle arrest at the G0/G1 phase. Furthermore, a high-dose DMF significantly increased the number of early apoptotic cells by increasing cleaved caspase-9 and proapoptotic protein Bax expression and decreased the ratio of Bcl-xL/Bax ( P < .01). Thus, our data demonstrated for the first time that DMF has dual effects on breast cancer cell behaviors depending upon its dose. Caution must be warranted in determining its effective dose for targeting breast cancer.

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Resuming Sensitivity of Tamoxifen-Resistant Breast Cancer Cells to Tamoxifen by Tetrandrine

Integrative Cancer Therapies ◽

10.1177/1534735421996822 ◽

2021 ◽

Vol 20 ◽

pp. 153473542199682

Author(s):

Yuntao Wang ◽

Wei Yue ◽

Haiyan Lang ◽

Xiaoqing Ding ◽

Xinyi Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Cancer Cell Line ◽

Development Of Resistance ◽

Apoptotic Effect ◽

Tamoxifen Resistant ◽

Mcf 7

Background: Tamoxifen is one of the medicines for adjuvant endocrine therapy of hormone-dependent breast cancer. However, development of resistance to tamoxifen occurs inevitably during treatment. This study aimed to determine whether sensitivity of tamoxifen-resistant breast cancer cells (TAM-R) could be reinstated by tetrandrine (Tet). Methods: All experiments were conducted in TAM-R cells derived from the MCF-7 breast cancer cell line by long-term tamoxifen exposure. Cell growth, apoptosis, and autophagy were end-points that evaluated the effect of Tet (0.9 μg/ml, 1.8 μg/ml, and 3.75 μg/ml) alone or in combination with TAM (1 μM). Cell apoptosis was determined by an ELISA assay and autophagy was determined by fluorescent staining using the Enzo autophagy detection kit. Immunoblotting was used to evaluate markers for apoptosis, autophagy, and related signal pathway molecules. Results: Growth of TAM-R cells was significantly inhibited by Tet. Combination of Tet with tamoxifen induced a greater inhibition on cell growth than tamoxifen alone, which was predominantly due to enhancement of pro-apoptotic effect of TAM by Tet. Autophagy was significantly inhibited in TAM-R cells treated with Tet plus TAM as shown by increased autophagosomes and the levels of LC3-II and p62. At 0.9 μg/ml, Tet increased the levels of both apoptosis and autophagy markers. Among them increase in p53 levels was more dramatic. Conclusions: Tet as a monotherapy inhibits TAM-R cells. Tet potentiates the pro-apoptotic effect of TAM via inhibition of autophagy.

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In vitro evaluation of estrogenic, antiestrogenic and antitumor effects of amentoflavone

Human & Experimental Toxicology ◽

10.1177/0960327121999454 ◽

2021 ◽

pp. 096032712199945

Author(s):

AT Aliyev ◽

S Ozcan-Sezer ◽

A Akdemir ◽

H Gurer-Orhan

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Antitumor Effects ◽

Antiestrogenic Activity ◽

Er Positive ◽

In Vivo Effects ◽

Mcf 7

Apigenin, a flavonoid, is reported to act as an estrogen receptor (ER) agonist and inhibit aromatase enzyme. However, amentoflavone, a biflavonoid bearing two apigenin molecules, has not been evaluated for its endocrine modulatory effects. Besides, it is highly consumed by young people to build muscles, enhance mood and lose weight. In the present study, apigenin was used as a reference molecule and ER mediated as well as ER-independent estrogenic/antiestrogenic activity of amentoflavone was investigated. Antitumor activity of amentoflavone was also investigated in both ER positive (MCF-7 BUS) and triple-negative (MDA-MB-231) breast cancer cells and its cytotoxicity was evaluated in human breast epithelial cells (MCF-10A). Our data confirmed ER agonist, aromatase inhibitory and cytotoxic effects of apigenin in breast cancer cells, where no ER mediated estrogenic effect and physiologically irrelevant, slight, aromatase inhibition was found for amentoflavone. Although selective cytotoxicity of amentoflavone was found in MCF-7 BUS cells, it does not seem to be an alternative to the present cytotoxic drugs. Therefore, neither an adverse effect, mediated by an estrogenic/antiestrogenic effect of amentoflavone nor a therapeutical benefit would be expected from amentoflavone. Further studies could be performed to investigate its in vivo effects.

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Induction of Apoptosis in MDA-MB-231 Cells Treated with the Methanol Extract of Lichen Physconia hokkaidensis

Journal of Fungi ◽

10.3390/jof7030188 ◽

2021 ◽

Vol 7 (3) ◽

pp. 188

Author(s):

Ji-In Noh ◽

Seul-Ki Mun ◽

Eui Hyeon Lim ◽

Hangun Kim ◽

Dong-Jo Chang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Prolonged Exposure ◽

Methanol Extract ◽

Growth Factor Receptor ◽

Annexin V ◽

Er Positive ◽

Her 2 ◽

Induction Of Apoptosis ◽

Mcf 7

Physconia hokkaidensis methanol extract (PHE) was studied to identify anticancer effects and reveal its mechanism of action by an analysis of cytotoxicity, cell cycles, and apoptosis biomarkers. PHE showed strong cytotoxicity in various cancer cells, including HL-60, HeLa, A549, Hep G2, AGS, MDA-MB-231, and MCF-7. Of these cell lines, the growth of MDA-MB-231 was concentration-dependently suppressed by PHE, but MCF-7 was not affected. MDA-MB-231 cells, triple-negative breast cancer (TNBC) cells, do not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), whereas MCF-7 cells are ER-positive, PR-positive, and HER-2-negative breast cancer cells. The number of cells in sub-G1 phase was increased after 24 h of treatment, and annexin V/PI staining showed that the population size of apoptotic cells was increased by prolonged exposure to PHE. Moreover, PHE treatment downregulated the transcriptional levels of Bcl-2, AMPK, and p-Akt, whereas it significantly upregulated the levels of cleaved caspase-3, cleaved caspase-9, and cleaved-PARP. In conclusion, it was confirmed that the PHE exhibited selective cytotoxicity toward MDA-MB-231, not toward MCF-7, and its cytotoxic activity is based on induction of apoptosis.

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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

Pharmaceuticals ◽

10.3390/ph14020169 ◽

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.

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