Abstract
PURPOSE: This study aimed to evaluate the effects of curcumin by co-administration of arsenic trioxide (As(2)O(3)) 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 As(2)O(3) 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 As(2)O(3) treatment of AML, and 48 targets in the curcumin combined with the As(2)O(3) 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 As(2)O(3) 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 As(2)O(3) treatment of AML. Moreover, the in vitro experiment demonstrated that curcumin combined with As(2)O(3) inhibited proliferation and induced apoptosis in KG1-a cells, and this effect is more substantial than curcumin or As(2)O(3) alone. Mechanistically, the curcumin combined with As(2)O(3) 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 As(2)O(3) group. CONCLUSION: Our results suggested that curcumin and As(2)O(3) combination therapy exerts more significant anti-leukemia effects in the treatment of AML than curcumin or As(2)O(3) monotherapy by up-regulating p53 pathway and down-regulating the JAK2/STAT3 pathway.