Anticancer Activity of Erianin: Cancer-Specific Target Prediction Based on Network Pharmacology

Abstract

Erianin is a major bisbenzyl compound extracted from Dendrobium chrysotoxum Lindl., an important traditional Chinese herb. In recent years, a growing body of evidence has proved the potential therapeutic effects of erianin on various cancers, including hepatoma, melanoma, non-small-cell lung carcinoma, myelogenous leukemia, breast cancer, and osteosarcoma. Especially, the pharmacological activities of erianin, such as antioxidant and anticancer activity, have been frequently demonstrated by plenty of studies. In this study, we firstly conducted a systematic review on reported anticancer activity of erianin. All updated valuable information regarding the underlying action mechanisms of erianin in specific cancer was recorded and summarized in this paper. Most importantly, based on the molecular structure of erianin, its potential molecular targets were analyzed and predicted by means of the SwissTargetPrediction online server (http://www.swisstargetprediction.ch). In the meantime, the potential therapeutic targets of 10 types of cancers in which erianin has been proved to have anticancer effects were also predicted via the Online Mendelian Inheritance in Man (OMIM) database (http://www.ncbi.nlm.nih.gov/omim). The overlapping targets may serve as valuable target candidates through which erianin exerts its anticancer activity. The clinical value of those targets was subsequently evaluated by analyzing their prognostic role in specific cancer using Kaplan-Meier plotter (http://Kmplot.com/analysis/) and Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn/). To better assess and verify the binding ability of erianin with its potential targets, molecular flexible docking was performed using Discovery Studio (DS). The valuable targets obtained from the above analysis and verification were further mapped to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway using the Database for Annotation, Visualization and Integrated Discovery (DAVID) (http://david.abcc.ncifcrf.gov/) to explore the possible signaling pathways disturbed/regulated by erianin. Furthermore, the in silico prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of erianin was also performed and provided in this paper. Overall, in this study, we aimed at 1) collecting all experiment-based important information regarding the anticancer effect and pharmacological mechanism of erianin, 2) providing the predicted therapeutic targets and signaling pathways that erianin might act on in cancers, and 3) especially providing in silico ADMET properties of erianin.

Keywords: ADMET; anticancer activity; erianin; molecular docking; target prediction.

FIGURE 1

Potential target prediction and analysis of the KEGG pathway, GO_BP, and target–target interaction. (A) Molecular structure of erianin; (B–C) overlapping target analysis by Venn diagrams; (D) KEGG pathway enrichment of the overlapping targets; (E) GO_biological process analysis of the overlapping targets; (F) target–target interaction of the overlapping targets analyzed by STRING.

FIGURE 2

Schematic of the PI3K–AKT signaling pathway. This figure shows the important cascades associated with the PI3K–AKT signaling pathway that involves in cell angiogenesis, proliferation, and apoptosis. The proteins marked in red represent the potential targets of erianin predicted in this study. The reported signaling pathways involved in anticancer mechanisms of erianin are framed in gray.

FIGURE 3

Schematic of the MAPK signaling pathway. This figure shows the important cascades associated with the MAPK signaling pathway that involves in angiogenesis and cancer cell proliferation. The proteins marked in red represent the potential targets of erianin predicted in this study. The reported signaling pathways involved in anticancer mechanisms of erianin are framed in gray.

FIGURE 4

Binding of erianin with (A) PI3K and (B) RET by molecular docking. Erianin exhibits high binding affinity to PI3K protein via sites of Trp292, Asp788, Arg690, His295, Trp201, Lys298, Leu864, and Glu852, and to RET protein via sites of Asp874, Asp892, Lys758, Leu730, Leu881, Val738, Val804, Ala756, Tyr806, and Ala807.

FIGURE 5

Binding of erianin with (A) KIT and (B) ABL1 by molecular docking. Erianin exhibits high binding affinity to KIT protein via sites of Ala621, Val603, Lys623, Leu644, Ile653, Ile808, Val643, Cys788, and Cys809, and to ABL1 protein via sites of Val299, Ile313, Lys271, Ala380, Ala269, Val256, Thr315, Tyr253, and Phe382.

FIGURE 6

(A) Binding of erianin with FLT3 by molecular docking. Erianin exhibits high binding affinity to FLT3 protein via sites of Glu573, Phe621, Tyr572, Ile836, Asp811, Pro851, Arg849, Tyr842, Ala848, and Tyr865. (B) ADMET plot, plotted by ADMET_PSA_2D vs. ADMET_AlogP98. The dark blue dots represent AlogP98 of each drug. The red and green ellipses represent 95 and 99% confidence intervals of the blood–brain barrier (BBB) permeability model, respectively, and the rose red and light blue ellipses represent 95 and 99% confidence intervals of the human intestinal absorption (HIA) model, respectively.

FIGURE 7

Correlation between predicted target expression and survival prognosis of specific cancers. (A–E) KM-plotter and (F) GEPIA were used to perform overall survival analyses of different cancers by corresponding gene expression.