scholarly journals A New Anti-Estrogen Discovery Platform Identifies FDA-Approved Imidazole Anti-Fungal Drugs as Bioactive Compounds against ERα Expressing Breast Cancer Cells

2021 ◽  
Vol 22 (6) ◽  
pp. 2915
Author(s):  
Manuela Cipolletti ◽  
Stefania Bartoloni ◽  
Claudia Busonero ◽  
Martina Parente ◽  
Stefano Leone ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bioactive Compounds ◽  
Estrogenic Activity ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Cellular Models ◽  
Cancer Models ◽  
17Β Estradiol ◽  
Approved Drugs ◽  
Anti Fungal

17β-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as “anti-estrogens”-like drugs. Remarkably, the present “anti-estrogen” discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.

scholarly journals Unexpected Impact of a Hepatitis C Virus Inhibitor on 17β-Estradiol Signaling in Breast Cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 3418 ◽  
Author(s):  
Stefania Bartoloni ◽  
Stefano Leone ◽  
Filippo Acconcia
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Drug Repurposing ◽  
Estrogen Receptor Α ◽  
Physiological Processes ◽  
17Β Estradiol ◽  
Approved Drugs ◽  
First Time

17β-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor α (ERα). E2:ERα signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ERα abundance. Indeed, the control of ERα levels is necessary for the effects of E2, and E2 itself induces ERα degradation and cell proliferation in parallel. Thus, the modulation of intracellular ERα levels is a critical parameter for E2-induced cell proliferation. Therefore, we used this parameter as a bait to identify compounds that influence ERα levels and E2-dependent proliferation in breast cancer (BC) cells from a library of Food and Drug Administration (FDA)-approved drugs. We found that telaprevir (Tel) reduces ERα levels and inhibits BC cell proliferation. Tel is an inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease, but its effect on E2:ERα signaling has not been investigated. Here, for the first time, we analyzed the effects of Tel on intracellular ERα levels and E2:ERα signaling to cell proliferation in different ERα-expressing BC cell lines. Overall, our findings demonstrate that Tel reduces intracellular ERα levels, deregulates E2:ERα signaling and inhibits E2-induced proliferation in BC cells and suggest the potential drug repurposing of Tel for the treatment of BC.

scholarly journals In silico screening for ERα downmodulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells

2018 ◽  
Author(s):  
Claudia Busonero ◽  
Stefano Leone ◽  
Fabrizio Bianchi ◽  
Filippo Acconcia
Keyword(s):  
Cell Proliferation ◽  
In Silico ◽  
Gene Signature ◽  
Estrogen Receptor Α ◽  
Normal Breast ◽  
Breast Cancers ◽  
Intracellular Content ◽  
High Fraction ◽  
Approved Drugs ◽  
Fda Approved Drugs

AbstractPurposeMost breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (i.e., ICI182,780-ICI). Unfortunately, a high fraction of ET-treated women relapses and become resistant to ET. Therefore, additional anti-BC drugs are needed. Recently, we proposed that the identification of novel anti-BC drugs can be achieved using the modulation of the ERα intracellular content in BC cells as a pharmacological target. Here, we searched for Food and Drug Administration (FDA)-approved drugs that potentially modify the ERα content in BC cells.MethodsWe screened in silico more than 60,000 compounds to identify FDA-approved drugs with a gene signature similar to that of ICI. We identified mitoxantrone and thioridazine and tested them in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells.ResultsMitoxantrone and thioridazine induced ERα downmodulation and prevented MCF-7 cell proliferation. Interestingly, while mitoxantrone was toxic for normal breast cells, thioridazine showed preferential activity toward BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα-expressing BC cells.ConclusionsWe suggest that the modulation of the ERα intracellular concentration in BC cells can also be robustly exploited in in silico screenings to identify anti-BC drugs and further demonstrate a re-purposing opportunity for thioridazine in primary and metastatic ET-resistant BC treatment.

scholarly journals Palmitoylation-dependent Estrogen Receptor α Membrane Localization: Regulation by 17β-Estradiol

2005 ◽  
Vol 16 (1) ◽  
pp. 231-237 ◽  
Author(s):  
Filippo Acconcia ◽  
Paolo Ascenzi ◽  
Alessio Bocedi ◽  
Enzo Spisni ◽  
Vittorio Tomasi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Plasma Membrane ◽  
Estrogen Receptor Α ◽  
Membrane Localization ◽  
Target Cells ◽  
Dependent Manner ◽  
Caveolin 1 ◽  
17Β Estradiol

A fraction of the nuclear estrogen receptor α (ERα) is localized to the plasma membrane region of 17β-estradiol (E2) target cells. We previously reported that ERα is a palmitoylated protein. To gain insight into the molecular mechanism of ERα residence at the plasma membrane, we tested both the role of palmitoylation and the impact of E2 stimulation on ERα membrane localization. The cancer cell lines expressing transfected or endogenous human ERα (HeLa and HepG2, respectively) or the ERα nonpalmitoylable Cys447Ala mutant transfected in HeLa cells were used as experimental models. We found that palmitoylation of ERα enacts ERα association with the plasma membrane, interaction with the membrane protein caveolin-1, and nongenomic activities, including activation of signaling pathways and cell proliferation (i.e., ERK and AKT activation, cyclin D1 promoter activity, DNA synthesis). Moreover, E2 reduces both ERα palmitoylation and its interaction with caveolin-1, in a time- and dose-dependent manner. These data point to the physiological role of ERα palmitoylation in the receptor localization to the cell membrane and in the regulation of the E2-induced cell proliferation.

scholarly journals Estrogenic Activity of Mycoestrogen (3β,5α,22E)-Ergost-22-en-3-ol via Estrogen Receptor α-Dependent Signaling Pathways in MCF-7 Cells

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 36
Author(s):  
Dahae Lee ◽  
Yuri Ko ◽  
Changhyun Pang ◽  
Yoon-Joo Ko ◽  
You-Kyoung Choi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Methanol Extract ◽  
Estrogenic Activity ◽  
Cancer Cell Line ◽  
Estrogen Receptor Α ◽  
Bile Secretion ◽  
Bioassay Guided Fractionation ◽  
Positive Breast Cancer Cell ◽  
Mcf 7

Armillariella tabescens (Scop.) Sing., a mushroom of the family Tricholomataceae, has been used in traditional oriental medicine to treat cholecystitis, improve bile secretion, and regulate bile-duct pressure. The present study evaluated the estrogen-like effects of A. tabescens using a cell-proliferation assay in an estrogen-receptor-positive breast cancer cell line (MCF-7). We found that the methanol extract of A. tabescens fruiting bodies promoted cell proliferation in MCF-7 cells. Using bioassay-guided fractionation of the methanol extract and chemical investigation, we isolated and identified four steroids and four fatty acids from the active fraction. All eight compounds were evaluated by E-screen assay for their estrogen-like effects in MCF-7 cells. Among the tested isolates, only (3β,5α,22E)-ergost-22-en-3-ol promoted cell proliferation in MCF-7 cells; this effect was mitigated by the ER antagonist, ICI 182,780. The mechanism underlying the estrogen-like effect of (3β,5α,22E)-ergost-22-en-3-ol was evaluated using Western blot analysis to detect the expression of extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K), Akt, and estrogen receptor α (ERα). We found that (3β,5α,22E)-ergost-22-en-3-ol induced an increase in phosphorylation of ERK, PI3K, Akt, and ERα. Together, these experimental results suggest that (3β,5α,22E)-ergost-22-en-3-ol is responsible for the estrogen-like effects of A. tabescens and may potentially aid control of estrogenic activity in menopause.

Estrogen receptor α L429 and A430 regulate 17β-estradiol-induced cell proliferation via CREB1

2015 ◽  
Vol 27 (12) ◽  
pp. 2380-2388 ◽  
Author(s):  
Valeria Pesiri ◽  
Pierangela Totta ◽  
Marco Segatto ◽  
Fabrizio Bianchi ◽  
Valentina Pallottini ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
17Β Estradiol

scholarly journals Lysosomal Function Is Involved in 17β-Estradiol-Induced Estrogen Receptor α Degradation and Cell Proliferation

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94880 ◽  
Author(s):  
Pierangela Totta ◽  
Valeria Pesiri ◽  
Maria Marino ◽  
Filippo Acconcia
Keyword(s):  
Cell Proliferation ◽  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Lysosomal Function ◽  
17Β Estradiol

scholarly journals Ouabain and Digoxin Activate the Proteasome and the Degradation of the ERα in Cells Modeling Primary and Metastatic Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3840
Author(s):  
Claudia Busonero ◽  
Stefano Leone ◽  
Fabrizio Bianchi ◽  
Elena Maspero ◽  
Marco Fiocchetti ◽  
...  
Keyword(s):  
Endocrine Therapy ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Estrogen Receptor Α ◽  
New Drugs ◽  
Gene Profiling ◽  
Breast Cancers ◽  
Expression Of Genes ◽  
Approved Drugs ◽  
In Cells

Estrogen receptor α expressing breast cancers (BC) are classically treated with endocrine therapy. Prolonged endocrine therapy often results in a metastatic disease (MBC), for which a standardized effective therapy is still lacking. Thus, new drugs are required for primary and metastatic BC treatment. Here, we report that the Food and Drug Administration (FDA)-approved drugs, ouabain and digoxin, induce ERα degradation and prevent proliferation in cells modeling primary and metastatic BC. Ouabain and digoxin activate the cellular proteasome, instigating ERα degradation, which causes the inhibition of 17β-estradiol signaling, induces the cell cycle blockade in the G2 phase, and triggers apoptosis. Remarkably, these effects are independent of the inhibition of the Na/K pump. The antiproliferative effects of ouabain and digoxin occur also in diverse cancer models (i.e., tumor spheroids and xenografts). Additionally, gene profiling analysis reveals that these drugs downregulate the expression of genes related to endocrine therapy resistance. Therefore, ouabain and digoxin behave as ‘anti-estrogen’-like drugs, and are appealing candidates for the treatment of primary and metastatic BCs.

scholarly journals A functional drug re-purposing screening identifies carfilzomib as a drug preventing 17β-estradiol: ERα signaling and cell proliferation in breast cancer cells

2017 ◽  
Author(s):  
Claudia Busonero ◽  
Stefano Leone ◽  
Cinzia Klemm ◽  
Filippo Acconcia
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Model ◽  
Acquired Resistance ◽  
Estrogen Receptor Α ◽  
Attractive Alternative ◽  
Novel Drugs ◽  
A Cell ◽  
17Β Estradiol ◽  
Cell Model System

AbstractMost cases of breast cancer (BC) are estrogen receptor α-positive (ERα+) at diagnosis. The presence of ERα drives the therapeutic approach for this disease, which often consists of endocrine therapy (ET). 4OH-Tamoxifen and faslodex (i.e., fulvestrant - ICI182,780) are two ETs that render tumor cells insensitive to 17β-estradiol (E2)-dependent proliferative stimuli and prevent BC progression. However, ET has limitations and serious failures in different tissues and organs. Thus, there is an urgent need to identify novel drugs to fight BC in the clinic. Re-positioning of old drugs for new clinical purposes is an attractive alternative for drug discovery. For this analysis, we focused on the modulation of intracellular ERα levels in BC cells as target for the screening of about 900 Food and Drug Administration (FDA) approved compounds that would hinder E2:ERα signaling and inhibit BC cell proliferation. We found that carfilzomib induces ERα degradation and prevents E2 signaling and cell proliferation in two ERα+ BC cell lines. Remarkably, the analysis of carfilzomib effects on a cell model system with an acquired resistance to 4OH-tamoxifen revealed that this drug has an antiproliferative effect superior to faslodex in BC cells. Therefore, our results identify carfilzomib as a drug preventing E2:ERα signaling and cell proliferation in BC cells and suggest its possible re-position for the treatment of ERα+ BC as well as for those diseases that have acquired resistance to 4OH-tamoxifen.

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