Cytotoxicity Of Chalcone Of Eugeniaaquea Burm F. Leaves Against T47D Breast Cancer Cell Lines And Its Prediction As An Estrogen Receptor Antagonist Based On Pharmacophore-Molecular Dynamics Simulation

Abstract

Background

The 2ʹ,4ʹ-dihydroxy-6-methoxy-3,5-3-dimethylchalcone (ChalcEA) isolated from Eugenia aquea Burm f. leaves has potential anticancer activity against human breast-adenocarcinoma cell lines (MCF-7) with an IC₅₀ value of 250 µM. However, its apoptotic activity on the T47D breast cancer cell lines which is involving caspase-3 has not been investigated.

Materials and methods

Therefore, this study aims to evaluate the cytotoxicity of ChalcEA on the T47D cell lines using the 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST) method and to predict its possible antagonistic activity on the human estrogen receptor alpha (hERα) using pharmacophore and molecular dynamics (MD) methods. The in vitro test of 10 synthesized ChalcEA derivatives was also performed as an insight into the further development of its structure as an anticancer agent.

Results

It is shown that ChalcEA has an IC₅₀ of 142.58 ± 4.6 µM against the hERα-overexpressed T47D breast cancer cell lines, indicating its possible mechanism of anticancer activity as an antagonist of hERα. Pharmacophore study showed that ChalcEA shares similar features with the known hERα antagonist, 4-hydroxytamoxifen (4-OHT), which has hydrogen bond donor (HBD), hydrogen bond acceptor (HBA), ring aromaticity (RA), and hydrophobicity (Hy) features. Molecular docking showed that ChalcEA formed hydrogen bonds with Glu353 and Arg394, and hydrophobic interactions in a similar manner with 4-OHT. Moreover, MD simulations showed that ChalcEA destabilized the conformation of His524, a remarkable behavior of a known hERa antagonist, including 4-OHT. Furthermore, the 10 best chalcone derivatives resulted from pharmacophore- and docking-based screening, were tested against the T47D cell lines. None of the derivatives have better activity than ChalcEA. It is suggested that the functional groups at the B-ring of ChalcEA are interesting to be further optimized in the next studies.

Conclusion

ChalcEA might act as an antagonist toward hERα, thus warranting further investigation as a potential anticancer agent.

Keywords:

• chalcone
• estrogen receptor
• pharmacophore
• molecular docking
• molecular dynamics

Acknowledgments

We gratefully acknowledge the Rector of Universitas Padjadjaran and the Minister of Research and Higher Education for funding this project through the Grant of Research and Publication 2016–2018 and Academic Leadership Grants 2019 no. 1373b/UN6.O/LT/2019 from Universitas Padjadjaran. We also acknowledge the support of IntelLigand Company for the use of their facilities.

Disclosure

The authors report no conflicts of interest in this work.