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Urolithin A: A promising selective estrogen receptor modulator and 27-hydroxycholesterol attenuator in breast cancer

Ravindran Vini1,2, Vishnu Sunil Jaikumar3, Viji Remadevi1,2

  • 1Cancer Research Program, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India.

Phytotherapy Research : PTR
|June 22, 2023
PubMed

Insights

Urolithin A (UA) counteracts harmful effects of 27-hydroxycholesterol (27-HC) in breast cancer. UA shows antiproliferative and estrogen receptor modulating effects, offering potential as a safe therapeutic agent.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • 27-hydroxycholesterol (27-HC) acts as an endogenous selective estrogen receptor modulator (SERM), contributing to estrogen receptor (ER)-mediated breast cancer progression.
  • Pomegranate extracts, rich in ellagitannins and ellagic acid, are metabolized by gut microbiota into urolithins, such as urolithin A (UA) and urolithin B (UB).
  • Urolithins have demonstrated beneficial properties, including antiproliferative and estrogenic activities, suggesting potential therapeutic applications.

Purpose of the Study:

  • To investigate the potential of urolithins, specifically UA, in antagonizing and counteracting the adverse effects of 27-HC in breast cancer cells.
  • To evaluate UA's impact on breast cancer cell proliferation, membrane potential, and apoptosis.
  • To assess UA's estrogen receptor alpha (ERα) modulation activity and its in vivo efficacy and safety.

Main Methods:

  • In vitro assays using breast cancer cells to assess the effects of UA on 27-HC-induced proliferation, membrane potential, and apoptosis.
  • Analysis of estrogen response element (ERE) transcriptional activity and estrogen-responsive gene modulation.
  • In vivo hollow fiber assay to evaluate UA's efficacy in reducing breast cancer cell viability and 27-HC-induced proliferation.
  • Assessment of UA's effects on uterine proliferation and blood biochemical parameters in vivo.

Main Results:

  • UA demonstrated significant antiproliferative capacity, attenuating 27-HC-induced proliferation in breast cancer cells.
  • UA induced apoptosis and loss of membrane potential in breast cancer cells.
  • UA exhibited SERM-like activity by inducing ERE transcriptional activity and modulating estrogen-responsive genes.
  • In vivo studies confirmed UA's ability to reduce breast cancer cell viability and counteract 27-HC effects without adverse effects on uterine proliferation or blood parameters.

Conclusions:

  • Urolithin A (UA) acts as a potent ERα modulator and 27-HC antagonist, showing promise in combating cholesterol-linked breast cancer.
  • UA possesses antiproliferative and apoptosis-inducing properties against breast cancer cells.
  • UA is safe and well-tolerated, indicating its potential as a therapeutic agent for estrogen-dependent conditions.
Keywords:
27-hydroxycholesterol (27-HC)breast cancerselective estrogen receptor modulator (SERM)urolithin A

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