Curcumin combined with arsenic trioxide in the treatment of acute myeloid leukemia: network pharmacology analysis and experimental validation.

PURPOSE: This study aimed to evaluate the effects of curcumin by co-administration of arsenic trioxide (As2O3) in acute myeloid leukemia (AML) treatment, using network pharmacology and experimental validation. METHODS: Using Pubchem database, Traditional Chinese Medicine Information Database (TCMID) database, and Swiss target prediction database to predict compound-related targets, AML-associated targets were determined using GeneCards and Online Mendelian Inheritance in Man (OMIM) databases. We identify overlapping common targets by comparing Compounds-related and AML-associated targets and using these targets to perform GO and KEGG functional enrichment analyses. Subsequently, these targets were input into the STRING database, and we used Cytoscape to construct protein-protein interaction (PPI) network. Finally, we used KG1-a cells and the AML mouse model to measure the anti-leukemia effects of curcumin and As2O3 and their combination. RESULTS: Compounds and targets screening hinted that 85 intersection targets were predicted in the curcumin treatment of AML, 75 targets in the As2O3 treatment of AML, and 48 targets in the curcumin combined with the As2O3 treatment of AML. GO and KEGG analyses indicated that the top 10 enriched biological processes and top 20 pathways implicated in the therapeutic effects of curcumin and As2O3 on AML, respectively. In addition, network pharmacology screening revealed STAT3, TP53, EP300, MAPK1, and PIK3CA as the top five genes in PPI network of curcumin treatment of AML and TP53, MAPK3, MAPK1, STAT3, and SRC as the top five genes in PPI network of As2O3 treatment of AML. Moreover, the in vitro experiment demonstrated that curcumin combined with As2O3 inhibited proliferation and induced apoptosis in KG1-a cells, and this effect is more substantial than curcumin or As2O3 alone. Mechanistically, the curcumin combined with As2O3 significantly down-regulated the protein expression of JAK2, STAT3, and Bcl-2, and up-regulated the levels of P53, P27, and Bax. In the mouse model, the survival time of mice in each administration group was drawn out to varying degrees, with the most significant prolongation in the curcumin combined with the As2O3 group. CONCLUSION: Our results suggested that curcumin and As2O3 combination therapy exerts more significant anti-leukemia effects in the treatment of AML than curcumin or As2O3 monotherapy by up-regulating p53 pathway and down-regulating the JAK2/STAT3 pathway.

Effects of Qinghuang Powder on Acute Myeloid Leukemia Based on Network Pharmacology, Molecular Docking, and In Vitro Experiments.

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.