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In silico estrogen receptor alpha antagonist studies and toxicity prediction of Melia azedarach leaves bioactive ethyl acetate fraction.

ABSTRACT: The estrogen hormone dependent accounts for a major cause in the incidence of women breast cancer. Thus, their receptor, especially the estrogen receptor α (ER-α), is becoming a target in endocrine treatment. These ligand-inducible nuclear functions are regulated by an array of phytochemical and synthetic compounds, such as 17 β-estradiol and tamoxifen (4-hydroxytamoxifen [4OHT]). The Chinaberry (Melia azedarach) leaves are known naturally for relieving internal and external diseases. Previous studies revealed the potency of Melia's ethanolic extract and ethyl acetate fractions as anticancer; furthermore, this study aimed to resolve possible ER-α antagonist's mechanism and safety from M. azedarach leaves ethyl acetate fraction contents. Melia's phytochemical content was analyzed with electrospray ionization liquid chromatography-mass spectrometry, while its ER-α antagonist's potency was investigated by in silico. The computational docking was used to 3ERT (a human ER-α-4OHT binding domain complex) with Autodock Vina and related programs. The results presented Energy binding (ΔG) of Melia's quercetin 3-O-(2'',6''-digalloyl)-β-D-galactopyranoside was similar to 4OHT, and lower than its agonist 17 β-estradiol. Furthermore, the toxicity prediction of these compounds were revealed safer than 4OHT. The Melia's leaves ethyl acetate fraction, therefore, is a potential pharmacological material for further studies.

SUBMITTER: Ervina M

PROVIDER: S-EPMC8300330 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:MAPK/ERK kinases transmit signals from many growth factors/kinase receptors during normal cell growth/differentiation, and their dysregulation is a hallmark of diverse types of cancers. A plethora of drugs were developed to block this kinase pathway for clinical application. With the exception of a recently identified agent, EQW, most of these inhibitors target upstream factors but not ERK1/2; no activator of ERK1/2 is currently available. METHOD:A library of compounds isolated from medicinal plants of China was screened for anti-cancer activities. Three limonoid compounds, termed A1541-43, originally isolated from the plant Melia azedarach, exhibiting strong anti-leukemic activity. The anti-neoplastic activity and the biological target of these compounds were explored using various methods, including western blotting, flow cytometry, molecular docking and animal model for leukemia. RESULTS:Compounds A1541-43, exhibiting potent anti-leukemic activity, was shown to induce ERK1/2 phosphorylation. In contrast, the natural product Cedrelone, which shares structural similarities with A1541-43, functions as a potent inhibitor of ERK1/2. We provided evidence that A1541-43 and Cedrelone specifically target ERK1/2, but not the upstream MAPK/ERK pathway. Computational docking analysis predicts that compounds A1541-43 bind a region in ERK1/2 that is distinct from that to which Cedrelone and EQW bind. Interestingly, both A1541-43, which act as ERK1/2 agonists, and Cedrelone, which inhibit these kinases, exerted strong anti-proliferative activity against multiple leukemic cell lines, and induced robust apoptosis as well as erythroid and megakaryocytic differentiation in erythroleukemic cell lines. These compounds also suppressed tumor progression in a mouse model of erythroleukemia. CONCLUSIONS:This study identifies for the first time activators of ERK1/2 with therapeutic potential for the treatment of cancers driven by dysregulation of the MAPK/ERK pathway and possibly for other disorders.

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In silico estrogen receptor alpha antagonist studies and toxicity prediction of Melia azedarach leaves bioactive ethyl acetate fraction.

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