Abstract
Fevicordin-A (FevA) isolated from Phaleria macrocarpa (Scheff) Boerl. seeds was evaluated for its potential anticancer activity by in vitro and in silico approaches. Cytotoxicity studies indicated that FevA was selective against cell lines of human breast adenocarcinoma (MCF-7) with an IC50 value of 6.4 μM. At 11.2 μM, FevA resulted in 76.8% cell death of T-47D human breast cancer cell lines. Critical pharmacophore features amongst human Estrogen Receptor-α (hERα) antagonists were conserved in FevA with regard to a hypothesis that they could make notable contributions to its pharmacological activity. The binding stability as well as the dynamic behavior of FevA towards the hERα receptor in agonist and antagonist binding sites were probed using molecular dynamics (MD) simulation approach. Analysis of MD simulation suggested that the tail of FevA was accountable for the repulsion of the C-terminal of Helix-11 (H11) in both agonist and antagonist receptor forms. The flexibility of loop-534 indicated the ability to disrupt the hydrogen bond zipper network between H3 and H11 in hERα. In addition, MM/GBSA calculation from the molecular dynamic simulations also revealed a stronger binding affinity of FevA in antagonistic action as compared to that of agonistic action. Collectively, both the experimental and computational results indicated that FevA has potential as a candidate for an anticancer agent, which is worth promoting for further preclinical evaluation.
Highlights
Breast cancer is the most common leading cause of cancer in women worldwide
MCF-7 and T-47D human breast cancer cell lines known to contain hERα [27,28] were used in this study
The cells were exposed to different concentrations of FevA (11.23, 22.45, 44.90, 89.81, and 179.62 μM) after 24 h up to 48 h
Summary
Breast cancer is the most common leading cause of cancer in women worldwide. According to the American Cancer Society, breast cancer represented 29% of cases (226,870) of all new cancer cases in the United States in 2012 [1]. Whilst in Malaysia, it is the cancer with the highest prevalence (26.5%) in women compared to other cancer types such as cervix, uterine, colorectal, lung, and ovary [3]. There are a number of risk factors for breast cancer identified which include socioeconomic status [4,5,6,7] and genetic factors [8,9]. Obesity or overweight, and oral contraception are said to significantly contribute to the risk of developing breast cancer [2]
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