Baba Mursaleen, Gor Ravi, Ramamurthy Chandrasudan, Mohideen Habeeb Shaik, Ramalingam Satish, Vijayakumar Thangavel Mahalingam
Department of Pharmacy Practice, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
Bioinformatics and Entomoinformatics lab, Department of Genetic Engineering, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu, 603203, India.
Anticancer Agents Med Chem. 2025 Apr 24. doi: 10.2174/0118715206377378250414052656.
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.
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.
Molecular docking identified phytochemicals targeting HIF-2α, with high-affinity compounds undergoing stability evaluation via GROMACS molecular dynamics simulations. ADMET and toxicity assessments were performed using SwissADME and ProTox-3.0. In-vitro assays on hypoxic MCF-7 cells examined cell viability and gene expression. The expression of HIF-2α-regulated genes (VEGFA, CCND1, GLUT1) was analyzed by using qRT-PCR.
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, Hbond 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 in vitro studies. It reduced cell viability with an IC50 of 118 μM and significantly downregulated HIF-2α-associated genes.
Morin demonstrated promising anti-cancer activity under hypoxic conditions by inhibiting HIF-2α in the hypoxia signaling pathway.
乳腺癌（BC）是一种常见的恶性肿瘤，对女性健康构成严重威胁。乳腺癌中的缺氧肿瘤微环境会促进耐药性，因此针对缺氧的治疗至关重要。靶向缺氧诱导因子（HIFs），尤其是HIF-2α，已成为抑制肿瘤生长并改善化疗和放疗反应的一种有前景的方法。然而，需要进一步研究以充分了解HIF-2α的作用，从而开发出更有效的乳腺癌治疗方法。
本研究的目的是鉴定靶向HIF-2α的植物化学物质，并评估它们在缺氧条件下对MCF-7乳腺癌细胞系的影响。
分子对接鉴定出靶向HIF-2α的植物化学物质，对具有高亲和力的化合物通过GROMACS分子动力学模拟进行稳定性评估。使用SwissADME和ProTox-3.0进行ADMET和毒性评估。对缺氧的MCF-7细胞进行体外试验，检测细胞活力和基因表达。使用qRT-PCR分析HIF-2α调控基因（VEGFA、CCND1、GLUT1）的表达。
分子对接显示，柚皮苷（-8.2千卡/摩尔）和桑色素（-7.1千卡/摩尔）比标准药物贝佐蒂芬（-7.7千卡/摩尔）表现出更好的结合亲和力。包括均方根偏差（RMSD）、均方根波动（RMSF）、氢键相互作用、回旋半径（Rg）、溶剂可及表面积（SASA）和势能（PE）在内的动力学模拟证实了它们强大的结合潜力。特别是桑色素表现出更多的氢键相互作用，并且符合Lipinski的五规则，使其成为体外研究的一个有前景的候选物。它以118μM的半数抑制浓度（IC50）降低细胞活力，并显著下调与HIF-2α相关的基因。
桑色素通过抑制缺氧信号通路中的HIF-2α，在缺氧条件下显示出有前景的抗癌活性。
