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

Claudia Busonero, Stefano Leone, Fabrizio Bianchi, Filippo Acconcia

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Purpose: Most breast cancers (BCs) express estrogen receptor α (ERα) and are treated with the endocrine therapy (ET) drugs 4OH-tamoxifen (Tam) and fulvestrant (ICI 182,780; ICI). Unfortunately, a high fraction of ET treated women relapses and becomes 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 modulation of the intracellular ERα 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. Methods: We 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. Results: We found that mitoxantrone and thioridazine induced ERα downmodulation and prevented MCF-7 BC cell proliferation. Interestingly, while mitoxantrone was found to be toxic for normal breast epithelial cells, thioridazine showed a preferential activity towards BC cells. Thioridazine also reduced the ERα content and prevented cell proliferation in primary, Tam-resistant and genome-edited Y537S ERα expressing BC cells. Conclusions: We suggest that modulation of the intracellular ERα concentration in BC cells can be exploited in in silico screens to identify anti-BC drugs and uncover a re-purposing opportunity for thioridazine in the treatment of primary and metastatic ET resistant BCs.

Original languageEnglish
Pages (from-to)677-686
Number of pages10
JournalCellular Oncology
Volume41
Issue number6
DOIs
Publication statusPublished - Dec 1 2018

Fingerprint

Thioridazine
Estrogen Receptor Modulators
Estrogen Receptors
Computer Simulation
Breast Neoplasms
Mitoxantrone
Pharmaceutical Preparations
United States Food and Drug Administration
Tamoxifen
afimoxifene
Cell Proliferation
Genome
Poisons
Therapeutics
Breast
Epithelial Cells

Keywords

  • Breast cancer
  • Degradation
  • Estrogen receptor
  • Mitoxantrone
  • Thioridazine
  • Y537S

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Cancer Research

Cite this

In silico screening for ERα down modulators identifies thioridazine as an anti-proliferative agent in primary, 4OH-tamoxifen-resistant and Y537S ERα-expressing breast cancer cells. / Busonero, Claudia; Leone, Stefano; Bianchi, Fabrizio; Acconcia, Filippo.

In: Cellular Oncology, Vol. 41, No. 6, 01.12.2018, p. 677-686.

Research output: Contribution to journalArticle

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