Artonin E and Structural Analogs from Artocarpus Species Abrogates Estrogen Receptor Signaling in Breast Cancer

Abstract

Abstract:The increasing rate of mortality ensued from breast cancer has encouraged research into safer and efficient therapy. The human Estrogen receptor α has been implicated in the majority of reported breast cancer cases. Molecular docking employing Glide, Schrodinger suite 2015, was used to study the binding affinities of small molecules from the Artocarpus species after their drug-like properties were ascertained. The structure of the ligand-binding domain of human Estrogen receptor α was retrieved from Protein Data Bank while the structures of compounds were collected from PubChem database. The binding interactions of the studied compounds were reported as well as their glide scores. The best glide scored ligand, was Artonin E with a score of´12.72 Kcal when compared to other studied phytomolecules and it evoked growth inhibition of an estrogen receptor positive breast cancer cells in submicromolar concentration (3.8-6.9 µM) in comparison to a reference standard Tamoxifen (18.9-24.1 µM) within the tested time point (24-72 h). The studied ligands, which had good interactions with the target receptor, were also drug-like when compared with 95% of orally available drugs with the exception of Artoelastin, whose predicted physicochemical properties rendered it less drug-like. The in silico physicochemical properties, docking interactions and growth inhibition of the best glide scorer are indications of the anti-breast cancer relevance of the studied molecules.

Artonin E induces p53-independent G1 cell cycle arrest and apoptosis through ROS-mediated mitochondrial pathway and livin suppression in MCF-7 cells

“…We previously reported the half-maximal growth inhibitory concentration (IC 50 ) of Artonin E-treated (Figure 1) MCF-7 cells at 24, 48, and 72 h as 3.8, 5.1, and 6.9 µM, respectively 14. For subsequent in vitro analysis, concentrations of 3, 10, and 30 µM were chosen.…”

“…The cell culture and growth inhibition assay were performed as previously reported 14. Briefly, the MCF-7 cells were acquired from the American Type Culture Collection (Manassas, VA, USA) and grown in Roswell Park Memorial Institute medium-1640 supplemented with 10% FBS and 1% penicillin–streptomycin.…”

“…The compound has also been shown to induce anoikis in lung cancer and to cause dysregulation of the mitochondrial membrane of ovarian cancer cells 7,13. More recently, Artonin E was computationally shown to abrogate estrogen receptor signaling in breast cancer and was conferred with the potential of inhibiting breast cancer using an in silico approach,14 but the mechanism of the predicted anti-breast cancer inhibition of this compound has not been reported. Hence, this study is aimed at investigating the mechanism of breast cancer cell death induced by Artonin E in an estrogen receptor-positive breast cancer cell line, MCF-7, being the most abundant type in breast cancer cases in a clinical setting 3,15,16…”

Isolation of Artonin E from the root bark of Artocarpus rigida, synthesis of Artonin E acetate and evaluation of anticancer activity

“…Some flavonoid compounds have been isolated from some species of Artocarpus and some of the compounds isolated have shown interesting biological activities [1][2][3][4][5][6]; one of the compounds is artonin E. Artonin E is a flavonoid compound which potential anticancer and antimalaria activity [7,8] and can easily be isolated from various Artocarpus plant such as A. communis, A. rotunda, A. altilis, A. elasticus and A. rigida [3,4,7,[9][10][11][12].…”

The molecular mechanism of the anticancer effect of Artonin E in MDA-MB 231 triple negative breast cancer cells

“…Artonin E, 5-hydroxy-8,8-dimethyl-3-(3-methylbut-2-enyl)-2-(2,4,5-trihydroxyphenyl) pyrano [2,3-h]chromen-4-one, is a prenylated flavonoid isolated from the stem bark of Artocarpus elasticus [ 18 ]. This compound has been shown to possess several biological activities including arachidonate 5-lipoxigenase inhibition, antibacterial and anticandicidal [ 19 ] antimalarial[ 20 ][ 21 ], anticancer [ 22 ][ 17 ] and antiestrogenic [ 23 ]. Recently, we reported the mitochondrial dysregulation of Artonin E in ovarian cancer [ 18 ] as well as its antiestrogenic capacity [ 23 ].…”