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

摘要

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.