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环境病理学,毒理学和肿瘤学期刊
影响因子: 1.625 5年影响因子: 1.63 SJR: 0.402 SNIP: 0.613 CiteScore™: 2.3

ISSN 打印: 0731-8898
ISSN 在线: 2162-6537

环境病理学,毒理学和肿瘤学期刊

DOI: 10.1615/JEnvironPatholToxicolOncol.2018024654
pages 331-339

Studying the in Silico Effect of Ellagic Acid on HIF-2α to Improve Efficacy of Anticancer Therapy

Vidhula Ahire
LARIA, iRCM, François Jacob Institute, DRF-CEA, Caen, France; UMR6252 CIMAP, CEA - CNRS– ENSICAEN, Université de Caen Normandie, Caen, France
Devashish Das
Durga Femto Technologies and Research, Bangalore, India
Shashank Arora
Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia
Anurag Kumar
Durga Femto Technologies and Research, Bangalore, India
Guruprasad Ramakrishna
Durga Femto Technologies and Research, Bangalore, India
Kaushala Prasad Mishra
Department of Life Sciences, University of Mumbai, Mumbai, India; Nehru Gram Bharati University, Allahabad, UP, India; Foundation for Education and Research, India and BM International Research Centre, Mumbai, India

ABSTRACT

The hypoxic tumor microenvironment is one of the major causes of the enhanced chemoresistant and radioresistant behavior of cancer cells. Therefore, the hypoxia-induced factor (HIF) pathway can be endorsed, for not only the malignant phenotype of the cells, but also its metastatic potential. Many drugs targeting the HIF pathways have failed in the clinical setting to demonstrate therapeutic efficacy. Such failures occur due to lack of specificity or redundancy in the complexity of tumor signaling/metabolism that can overcome the inhibitory effects. Another important factor is the letdown of the compound that can be accredited to lack of patient selection in the trials. Although many clinical trials have evaluated the efficacy of anticancer therapeutics and examined their effects on HIF levels, patients were not selected based on their HIF expression levels. If patients do not have elevated levels of HIF, then the therapeutics that target the HIF pathway may be less effective. In the present work, we have targeted HIF-2α of the HIF pathway. Ellagic acid (EA), a well-known anticancer compound and radiosensitizer, is used to inhibit the activity of HIF-2α. Our results show a very unique binding of EA with HIF-2α. Such new agents should be used in combination therapy and will hopefully overcome the resistance that may develop during initial treatment if the patient is identified to have enhanced expression of HIF-2α. Molecular dynamics studies followed solvation free energy calculations (molecular mechanics Poisson-Boltzmann surface area) for understanding the binding stability and per residue contribution. Our in silico data look promising and EA should be studied more in in vitro and in vivo for further analysis of its efficacy.


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