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2000
Volume 25, Issue 17
  • ISSN: 1871-5206
  • E-ISSN: 1875-5992

Abstract

Background

Breast cancer (BC) is a common malignancy that poses a serious threat to women's health. The hypoxic tumor microenvironment in BC promotes drug resistance, making hypoxia-targeted therapies crucial. Targeting hypoxia-inducible factors (HIFs), particularly HIF-2α, has emerged as a promising approach to inhibit tumor growth and improve response to chemotherapy and radiotherapy. However, further research is required to fully understand the role of HIF-2α to develop more effective treatments for BC.

Aims

The aim of this study is to identify phytochemicals that target HIF-2α and evaluate their effects on the MCF-7 breast cancer cell line under hypoxic conditions.

Methods

Molecular docking identified phytochemicals targeting HIF-2α, with high-affinity compounds undergoing stability evaluation GROMACS molecular dynamics simulations. ADMET and toxicity assessments were performed using SwissADME and ProTox-3.0. assays on hypoxic MCF-7 cells examined cell viability and gene expression. The expression of HIF-2α-regulated genes () was analyzed by using qRT-PCR.

Results

Molecular docking revealed that naringin (-8.2 Kcal/mol) and morin (-7.1 Kcal/mol) showed better binding affinity than the standard drug, belzutifan (-7.7 Kcal/mol). Dynamic simulations, including RMSD, RMSF, H-bond interactions, Rg, SASA, and PE, confirmed their strong binding potential. Morin, in particular, demonstrated more H-bond interactions and met Lipinski's Rule of Five, making it a promising candidate for studies. It reduced cell viability with an IC of 118 µM and significantly downregulated HIF-2α-associated genes.

Conclusion

Morin demonstrated promising anti-cancer activity under hypoxic conditions by inhibiting HIF-2α in the hypoxia signaling pathway.

© 2025 Bentham Science Publishers
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2025-09-10

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Identification of Flavonoid-based Hypoxia-inducible Factor-2 Alpha Inhibitors for the Treatment of Breast Cancer– In silico and In vitro Evidence
Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) 25, 1359 (2025); https://doi.org/10.2174/0118715206377378250414052656
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  • Article Type:     Research Article
Keyword(s): breast cancer; hypoxia; hypoxia-inducible factor; Hypoxia-inducible factor-2α; MCF-7 cell line; molecular docking; morin; phytochemicals

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