Abstract：
With high incidence of hepatocarcinoma and limited effective treatments, most patients suffer in pain. Antitumor drugs are single-targeted, toxicity, causing adverse side effects and resistance. Dihydroartemisinin (DHA) inhibits tumor through multiple mechanisms effectively. This study explores and evaluates safety and potential mechanism of DHA towards human hepatocarcinoma based on network pharmacology in a comprehensive way. Adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of DHA were evaluated with pkCSM, SwissADME, and ADMETlab. Potential targets of DHA were obtained from SwissTargetPrediction, Drugbank, TargetNET, and PharmMapper. Target gene of hepatocarcinoma was obtained from OMIM, GeneCards, and DisGeNET. Overlapping targets and hub genes were identified and analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway. Molecular docking was utilized to investigate the interactions sites and hydrogen bonds. Cell counting kit-8 (CCK8), wound healing, invasion, and migration assays on HepG2 and SNU387 cell proved DHA inhibits malignant biological features of hepatocarcinoma cell. DHA is safe and desirable for clinical application. A total of 131 overlapping targets were identified. Biofunction analysis showed targets were involved in kinase activity, protein phosphorylation, intracellular reception, signal transduction, transcriptome dysregulation, PPAR pathway, and JAK-STAT signaling axis. Top 9 hub genes were obtained using MCC (Maximal Clique Centrality) algorithm, namely CDK1, CCNA2, CCNB1, CCNB2, KIF11, CHEK1, TYMS, AURKA, and TOP2A. Molecular docking suggests that all hub genes form a stable interaction with DHA for optimal binding energy were all less than - 5 kcal/mol. Dihydroartemisinin might be a potent and safe anticarcinogen based on its biological safety and effective therapeutic effect.
摘要：
肝癌发病率高,有效的治疗方法有限,大多数病人痛苦。抗肿瘤药物是单靶向的,毒性,引起不良副作用和抗性。双氢青蒿素(DHA)通过多种机制有效抑制肿瘤。本研究从网络药理学的角度全面探索和评价DHA对人肝癌的安全性和潜在作用机制。吸附,分布，新陈代谢，排泄,DHA的毒性(ADMET)特性用pkCSM进行了评价，Swissadme,和ADMETlab。DHA的潜在靶标来自SwissTargetPrediction，药店,TargetNET,和PharmMapper.从OMIM获得肝癌的靶基因，GeneCards,和DisGeNet。对重叠的靶标和枢纽基因进行了鉴定和基因本体论(GO)分析，京都基因和基因组百科全书（KEGG），和Reactome途径。分子对接用于研究相互作用位点和氢键。细胞计数试剂盒-8(CCK8),伤口愈合，入侵,HepG2和SNU387细胞的迁移实验证明DHA抑制肝癌细胞的恶性生物学特征。DHA是安全的并且对于临床应用是理想的。总共确定了131个重叠的目标。生物功能分析显示，目标与激酶活性有关，蛋白质磷酸化，细胞内接收，信号转导，转录组失调，PPAR途径,和JAK-STAT信号轴。使用MCC（最大集团中心性）算法获得了前9个hub基因，即CDK1，CCNA2，CCNB1，CCNB2，KIF11，CHEK1，TYMS，Aurka,TOP2A分子对接表明，所有hub基因与DHA形成稳定的相互作用，最佳结合能均小于-5kcal/mol。基于双氢青蒿素的生物安全性和有效的治疗作用，双氢青蒿素可能是一种有效且安全的抗癌药物。
