On the Mechanism of Wogonin Against Acute Monocytic Leukemia Using Network Pharmacology and Experimental Validation

Overview

Journal Sci Rep

Specialty Science

Date 2024 May 2

PMID 38698063

Authors

Xixi Wang

Yanfei Wang

Jing Chen

Qinyao Wang

Zhongjian Liu

Yijie Yin

Tonghua Yang

Tao Shen

Yalian Sa

Affiliations

Soon will be listed here.

Abstract

Wogonin is a natural flavone compound from the plant Scutellaria baicalensis, which has a variety of pharmacological activities such as anti-cancer, anti-virus, anti-inflammatory, and immune regulation. However, the potential mechanism of wogonin remains unknown. This study was to confirm the molecular mechanism of wogonin for acute monocytic leukemia treatment, known as AML-M5. The potential action targets between wogonin and acute monocytic leukemia were predicted from databases. The compound-target-pathway network and protein-protein interaction network (PPI) were constructed. The enrichment analysis of related targets and molecular docking were performed. The network pharmacological results of wogonin for AML-M5 treatment were verified using the THP-1 cell line. 71 target genes of wogonin associated with AML-M5 were found. The key genes TP53, SRC, AKT1, RELA, HSP90AA1, JUN, PIK3R1, and CCND1 were preliminarily found to be the potential central targets of wogonin for AML-M5 treatment. The PPI network analysis, GO analysis and KEGG pathway enrichment analysis demonstrated that the PI3K/AKT signaling pathway was the significant pathway in the wogonin for AML-M5 treatment. The antiproliferative effects of wogonin on THP-1 cells of AML-M5 presented a dose-dependent and time-dependent manner, inducing apoptosis, blocking the cell cycle at the G2/M phase, decreasing the expressions of CCND1, CDK2, and CyclinA2 mRNA, as well as AKT and p-AKT proteins. The mechanisms of wogonin on AML-M5 treatment may be associated with inhibiting cell proliferation and regulating the cell cycle via the PI3K/AKT signaling pathway.

References

Safran M, Chalifa-Caspi V, Shmueli O, Olender T, Lapidot M, Rosen N . Human Gene-Centric Databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE. Nucleic Acids Res. 2003; 31(1):142-6. PMC: 165497. DOI: 10.1093/nar/gkg050. View

. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2022; 51(D1):D523-D531. PMC: 9825514. DOI: 10.1093/nar/gkac1052. View

Cao H, Gao Y, Wang R, Guo Q, Hui H . Wogonin reverses the drug resistance of chronic myelogenous leukemia cells to imatinib through CXCL12-CXCR4/7 axis in bone marrow microenvironment. Ann Transl Med. 2020; 8(17):1046. PMC: 7575956. DOI: 10.21037/atm-20-1166. View

Morris G, Huey R, Lindstrom W, Sanner M, Belew R, Goodsell D . AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009; 30(16):2785-91. PMC: 2760638. DOI: 10.1002/jcc.21256. View

Hu C, Xu M, Qin R, Chen W, Xu X . Wogonin induces apoptosis and endoplasmic reticulum stress in HL-60 leukemia cells through inhibition of the PI3K-AKT signaling pathway. Oncol Rep. 2015; 33(6):3146-54. DOI: 10.3892/or.2015.3896. View

Pinero J, Bravo A, Queralt-Rosinach N, Gutierrez-Sacristan A, Deu-Pons J, Centeno E . DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Res. 2016; 45(D1):D833-D839. PMC: 5210640. DOI: 10.1093/nar/gkw943. View

Durr C, Hanna B, Schulz A, Lucas F, Zucknick M, Benner A . Tumor necrosis factor receptor signaling is a driver of chronic lymphocytic leukemia that can be therapeutically targeted by the flavonoid wogonin. Haematologica. 2018; 103(4):688-697. PMC: 5865430. DOI: 10.3324/haematol.2017.177808. View

Zhang H, Tian F, Jiang P, Qian S, Dai X, Ma B . Solasonine Suppresses the Proliferation of Acute Monocytic Leukemia Through the Activation of the AMPK/FOXO3A Axis. Front Oncol. 2021; 10:614067. PMC: 7879981. DOI: 10.3389/fonc.2020.614067. View

Kantarjian H, Kadia T, DiNardo C, Welch M, Ravandi F . Acute myeloid leukemia: Treatment and research outlook for 2021 and the MD Anderson approach. Cancer. 2021; 127(8):1186-1207. DOI: 10.1002/cncr.33477. View

10.

Kanehisa M . Toward understanding the origin and evolution of cellular organisms. Protein Sci. 2019; 28(11):1947-1951. PMC: 6798127. DOI: 10.1002/pro.3715. View

11.

Chinen Y, Tsukamoto T, Maegawa-Matsui S, Matsumura-Kimoto Y, Takimoto-Shimomura T, Tanba K . Tumor-specific transcript variants of cyclin D1 in mantle cell lymphoma and multiple myeloma with chromosome 11q13 abnormalities. Exp Hematol. 2020; 84:45-53.e1. DOI: 10.1016/j.exphem.2020.02.004. View

12.

Xu W, Wu H, Chen S, Wang X, Tanaka S, Sugiyama K . Cytotoxic effects of vitamins K1, K2, and K3 against human T lymphoblastoid leukemia cells through apoptosis induction and cell cycle arrest. Chem Biol Drug Des. 2020; 96(4):1134-1147. DOI: 10.1111/cbdd.13696. View

13.

Ru J, Li P, Wang J, Zhou W, Li B, Huang C . TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform. 2014; 6:13. PMC: 4001360. DOI: 10.1186/1758-2946-6-13. View

14.

Xue C, Li G, Lu J, Li L . Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther. 2021; 6(1):400. PMC: 8611092. DOI: 10.1038/s41392-021-00788-w. View

15.

Huang Q, Wang L, Ran Q, Wang J, Wang C, He H . Notopterol-induced apoptosis and differentiation in human acute myeloid leukemia HL-60 cells. Drug Des Devel Ther. 2019; 13:1927-1940. PMC: 6560190. DOI: 10.2147/DDDT.S189969. View

16.

Guo D, Gu M, Du F, Zhao Y, Gao M, Hao J . Review of molecular biological studies on acute lymphoblastic leukemia treated by modified shengmaiyin. Medicine (Baltimore). 2023; 102(23):e34013. PMC: 10256333. DOI: 10.1097/MD.0000000000034013. View

17.

Zhu T, Wang L, Feng Y, Sun G, Sun X . Classical Active Ingredients and Extracts of Chinese Herbal Medicines: Pharmacokinetics, Pharmacodynamics, and Molecular Mechanisms for Ischemic Stroke. Oxid Med Cell Longev. 2021; 2021:8868941. PMC: 7984881. DOI: 10.1155/2021/8868941. View

18.

Sanner M . Python: a programming language for software integration and development. J Mol Graph Model. 2000; 17(1):57-61. View

19.

Sherman B, Hao M, Qiu J, Jiao X, Baseler M, Lane H . DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022; 50(W1):W216-W221. PMC: 9252805. DOI: 10.1093/nar/gkac194. View

20.

Lin X, Tian D, Fu Y, Li Y, Huang L, Gu W . Synthesis of novel guttiferone E and xanthochymol derivatives with cytotoxicities by inducing cell apoptosis and arresting the cell cycle phase. Eur J Med Chem. 2018; 162:765-780. DOI: 10.1016/j.ejmech.2018.11.046. View