Chinese medicine has a good effect and a long history for the treatment of various complex illness. In the research of active pharmaceutical ingredients, the method based on network interactions is of great help in deepening the understanding of the role of drugs in multi-layer information(29). The interaction network of drugs, active ingredients, diseases and target proteins is an important way to express the mechanism of drugs and their active ingredients in the treatment of a certain disease, which helps to deepen the understanding of the therapeutic effects of drugs and offer a theoretical basis for new drugs development(30). As an important pharmacological research method, network pharmacology can better demonstrate the relationship between drugs, components and targets. The application of this idea in the research of traditional Chinese medicine can help to understand the interaction mechanism of multi-component multi-target model of traditional Chinese medicine(31).
In this research, by taking the intersection of the active ingredient target of TW and the target of AML treatment, we obtained 37 target genes and eight active compounds. In these eight active compounds, Triptolide has been shown to have a therapeutic effect on AML (9, 32). Triptolide can inhibit the expression of MDM2 and thereby inhibit the p53-dependent pathway to achieve the curative effect on AML (33). Other active ingredients in TW have also been shown to have therapeutic effects on other cancers. Such as Hederagenin, it can inhibit the proliferation of cervical cancer CaSki cells and promote their apoptosis by blocking the STAT3 pathway(34). And Isoxanthohumol can inhibit the formation of lung metastasis in B16-F10 murine melanoma model (35). Tripterygium also exhibited significant inhibitory effects on many cancer cells (36) .
On the other hand, it can be seen from the D-C-G-D Network that these active ingredients have a common target, which shows that they have some synergistic effects in the treatment of AML. As one of the predicted targets of TW for the treatment of AML, PTGS2 can be acted by 7 active compounds in TW. It has been reported that it can selectively inhibit cox-2 and play a role in the treatment of AML (36–38). This means that multiple active ingredients in traditional Chinese medicine can act on a single target to take effect in the treatment of diseases. As for the active component, Triptolide is associated with 25 target genes, such as PTGS2, CD40, CASP3, JUN, etc., which is consistent with the fact that a single active compound can act on multiple targets.
In order to clarify the impact of these genes on the survival and prognosis of patients, we conducted a survival analysis of these 37 genes. The results show that some of these genes have a significant impact on the survival and prognosis of patients. And some genes have been experimentally proven to be the target of TW treatment of diseases such as AR, CD14, BCL2 (39–41). This means that these genes may be the crucial target of TW in the treatment of leukemia.
Next, we conducted GO and KEGG enrichment analysis on these target genes. The major signaling pathways related to AML were found to include: Pathways in cancer, Toll-like receptor signaling pathway, NF-kappa B signaling pathway, Transcriptional misregulation in cancer, HIF-1 signaling pathway, and other pathways closely connected to the occurrence and development of AML. This indicates that Tripterygium wilfordii may have multiple active ingredients through multiple pathways to prevent and treat AML. Such as Toll-like receptor signaling pathway, as a part of the innate immune system, studies have shown that various hematological malignant cells, including AML cells, express TLRs, and TLR agonists may directiy effect on the leukemic cells(38). Due to the indirect anti-leukemia effect caused by the activation / stimulation of normal immuneocompetent cells, such as eradicating residual leukemia cells after induction therapy, TLR is considered a possible drug target in AML(42). In addition, the release of pro-inflammatory cytokines due to TLR stimulation can enhance the immunogenicity of AML blasts, making it easier to treat(43). It is well known that in most patients with AML, NF-κB is constitutively activated, which helps to resist apoptosis. Studies have shown that inhibiting NF-κB can induce apoptosis in AML cells(44). Studies have shown that HIF1α promotes the proliferation of AML cells through a pro-tumoral chemokine factor signaling pathway(45).
Due to the complexity of traditional Chinese medicine ingredients and the limitations of experimental research methods, there are no reports on the effective ingredients, targets and mechanisms of TW for AML treatment. This study shows that using network pharmacology to study the effective ingredients and therapeutic targets of TW in the treatment of AML is of great significance for deepening the understanding of its related mechanism of action and discovering new effective ingredients. For the first time, the multi-targets and multi-pathways that play a role in AML are used to explain the molecular mechanism of Tripterygium wilfordii’s therapeutic effect. However, the pathogenesis of AML is more complicated. Signaling pathways cross and regulate each other, presenting a pattern of multiple pathways and multiple targets. In-depth analysis of the anti-AML pharmacological actions of Tripterygium wilfordii, as well as the targets and pathways of the active ingredients are necessary to be further verified.