Abstract
Qinghuang powder (QHP) is a traditional Chinese herbal medicine. This is a unique formula that is frequently used to treat malignant hematological diseases such as acute myeloid leukemia (AML) in modern clinical practice. An approach of network pharmacology and experimental validation were applied to investigate the pharmacological mechanisms of QHP in AML treatment. First, public databases for target genes known to be associated with AML are searched and compared to the target genes of the active compounds in QHP. Second, AML-associated genes and QHP target genes are compared to identify overlapping enriched genes, and these were used to predict selected target genes that may be implicated in the effects of QHP on AML. Additionally, we conducted functional enrichment analyses, such as gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The significantly enriched pathway associated with potential target proteins was the PI3K-Akt signaling pathway, suggesting that these potential target proteins and pathways may mediate the beneficial biological effects of QHP on AML. All these following genes were found to occur in the compounds-target-pathway networks: AKT1, MAPK1, MAPK3, PIK3CG, CASP3, CASP9, TNF, TGFB1, MAPK8, and TP53. Then, based on the molecular docking studies, it was suggested that the active compound isovitexin can fit into the binding pockets of the top candidate QHP-AML target proteins (PIK3CG). Subsequently, based on the prediction by network pharmacology analysis, both in vitro AML cells and western blot experiments were performed to validate the curative role of QHP. QHP exerted its antitumor activity on AML in vitro, as it inhibits cells proliferation, reduced the expression of Bcl-2 protein, and downregulated the PI3K-Akt signaling pathway. In conclusion, these results revealed that QHP could treat AML via a “multicomponent, multitarget, multipathway” regulatory network. Furthermore, our study also demonstrated that the combination of network pharmacology with the experimental study is effective in discovering and identifying QHP in the treatment of AML and its underlying pharmacological mechanisms.
Highlights
Acute myeloid leukemia (AML) is an aggressive malignancy worldwide with a poor prognosis
We identified a total of 48 compounds in Qinghuang powder (QHP) through the TCM Systematic Pharmacology Database [23] (TCMSP), TCM Integrated Database [24] (TCMID), and Symptom Mapping Database [22] (SymMap) databases, 38 of which were contained in Indigo Naturalis and 10 in Realgar
Among the 38 compounds in Indigo Naturalis, 8 (26.3%) met the requirement of oral bioavailability (OB) ≥ 30% and DL ≥ 0.18 based on the TCMSP database, and the 4 compounds in Realgar met this criterion based on the TCMID and SymMap databases. erefore, 14 compounds were chosen as candidate active compounds for further analysis
Summary
Acute myeloid leukemia (AML) is an aggressive malignancy worldwide with a poor prognosis. It is a relatively rare type of cancer (statistically accounting for 1.1% of all new cancer cases), with an estimated 19, 940 new cases in the United States in 2020, according to the NIH (National Institutes of Health) and SEER (Surveillance, Epidemiology, and End Results) databases. AML is characterized by the rapid proliferation of immature myeloid leukemia cells [1]. Most patients suffering from AML are struggling for life every day because it has the lowest overall survival rate of all cancer, in spite of aggressive treatments with chemotherapy. One of the biggest obstacles in AML treatment is the high relapsing rate despite a positive response to chemotherapy. The action of these drugs can suppress the progression of AML and is associated with several adverse side
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