Aspirin as a potential drug repurposing candidate targeting estrogen receptor alpha in breast cancer: a molecular dynamics and in-vitro study

Abstract

Estrogen receptor alpha (ERα) is expressed by 70% of breast cancers (BCs). Any deregulation in ERα signaling is crucial for the initiation and progression of BC. Because of development of resistance to anti-estrogenic compounds, repurposing existing drugs is an apt strategy to avoid a long drug-discovery process. Substantial epidemiologic evidence suggests that Aspirin use reduces the risk of different cancers including BC, while its role as an adjuvant or a possible antineoplastic agent in cancer treatment is being investigated. In this study, we attempted to explore possibilities of ERα inhibition by Aspirin which may act through competitive binding to the ligand binding domain (LBD) of ERα. A list of 48 ERα-LBD crystal structures bound with agonists, antagonists, and selective ER modulators (SERMs) was thoroughly analysed to determine interaction patterns specific to each ligand category. Exhaustive docking and 500 ns molecular dynamics (MD) studies were performed on three ERα - Aspirin complexes generated using agonist, antagonist, and SERM-bound crystal structures. Besides, three ERα crystal structures bound to agonist, antagonist, and SERM respectively were also subjected to MD simulations. Aspirin showed good affinity to LBD of ERα. Comparative analyses of binding patterns, conformational changes and molecular interaction profiles from the docking results and MD trajectories suggests that Aspirin was most stable in complex generated using SERM bound crystal structure of ERα and showed interactions with Gly-521, Ala-350, Leu-525 and Thr-347 like SERMs. In addition, in-vitro assays, qPCR, and immunofluorescent assay demonstrated the decline in the expression of ERα in MCF-7 upon treatment with Aspirin. These preliminary bioinformatical and in-vitro findings may form the basis to consider Aspirin as a potential candidate for targeting ERα, especially in tamoxifen-resistant cancers.

Communicated by Ramaswamy H. Sarma

Keywords:

• Breast cancer
• estrogen receptor alpha
• aspirin
• molecular docking
• molecular dynamics simulations
• agonists
• antagonists
• SERMs
• drug repurposing

Acknowledgments

DK acknowledges the University Grants Commission, India for providing financial support in the form of Senior Research Fellowship. CC thanks the Department of Science and Technology for financial assistance in the form of DST-INSPIRE Faculty award (IFA16-LSBM-170) and Schrodinger for providing short term licences for some of the modules. RY acknowledges CSIR, New Delhi for providing Senior Research Fellowship. LK acknowledges the University Grants Commission, India for providing financial support in the form of Senior Research Fellowship.

Authors’ contributions

DK and CC contributed to the designing of the study, performed bioinformatical work, analysis, interpretation of the results and drafting the final version of the manuscript. DK, RY and LK contributed to wet lab experimental work, designing, and drafting the final version of the manuscript. AB has contributed to the conceptualization, designing, drafting and approval of the final version of the manuscript.

Disclosure statement

The authors declare that there is no conflict of interest.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.