Department of Laboratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Tongji University Cancer Center, School of Medicine, Tongji University, Shanghai, 200092, China.
Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct;397(10):7711-7724. doi: 10.1007/s00210-024-03123-6. Epub 2024 May 7.
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.
由于肝癌发病率高，有效治疗方法有限，大多数患者都在痛苦中挣扎。抗肿瘤药物是单靶点的，毒性大，会导致不良反应和耐药性。二氢青蒿素（DHA）通过多种机制有效抑制肿瘤。本研究通过网络药理学全面探讨和评估 DHA 对人肝癌的安全性和潜在机制。利用 pkCSM、SwissADME 和 ADMETlab 评估 DHA 的吸收、分布、代谢、排泄和毒性（ADMET）特性。从 SwissTargetPrediction、Drugbank、TargetNET 和 PharmMapper 获得 DHA 的潜在靶点。从 OMIM、GeneCards 和 DisGeNET 获得肝癌的靶基因。通过基因本体论（GO）、京都基因与基因组百科全书（KEGG）和反应组通路对重叠靶点和枢纽基因进行识别和分析。利用分子对接研究相互作用位点和氢键。CCK8、划痕愈合、侵袭和迁移实验证明 DHA 抑制肝癌细胞的恶性生物学特征。DHA 安全且适合临床应用。共鉴定出 131 个重叠靶点。生物功能分析表明，这些靶点参与激酶活性、蛋白磷酸化、细胞内受体、信号转导、转录组失调、PPAR 通路和 JAK-STAT 信号轴。使用最大团块中心度（MCC）算法获得了 9 个主要枢纽基因，分别为 CDK1、CCNA2、CCNB1、CCNB2、KIF11、CHEK1、TYMS、AURKA 和 TOP2A。分子对接表明，所有枢纽基因均与 DHA 形成稳定的相互作用，最佳结合能均小于-5 kcal/mol。二氢青蒿素可能是一种有效的、安全的抗癌剂，具有良好的生物安全性和治疗效果。
