Prostate cancer (PCa) has high morbidity and mortality rates in elderly men. With a history of thousands of years, traditional Chinese medicine derived from insects could be an important source for developing cancer-targeted drugs to prevent tumorigenesis, enhance therapeutic effects, and reduce the risk of recurrence and metastasis. Multiple studies have shown that Coridius chinensis (Cc) has anticancer effects.

To elucidate the mechanism of action of Cc against PCa via network pharmacology and molecular docking.

Potential targets for Cc and PCa were predicted using ChemDraw 19.0 software, the PharmMapper database and the GeneCards database. Then, the STRING database was used to construct the protein–protein interaction network. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment and molecular docking analyses were subsequently conducted to identify the key targets, active ingredients and pathways involved.

GO and KEGG analyses indicated that the PI3K-Akt signalling pathway was the critical pathway (P value < 1.0 × 10^-8). Multiple targeting ingredients that can affect multiple pathways in PCa have been identified in Cc. Seven active compounds (asponguanosines A, asponguanine B, asponguanine C, aspongpyrazine A, N-acetyldopamine, aspongadenine B and aspongpyrazine B) were selected for molecular docking with 9 potential targets, and the results revealed that aspongpyrazine A and asponguanosine A are the main components by which Cc affects PCa (affinity<-5 kcal/mol, hydrogen bonding), but more studies are needed.

We used network pharmacology to predict the bioactive components and important targets of Cc for the treatment of PCa, supporting the development of Cc as a natural anticancer agent.

Prostate cancer (PCa) is a common cancer in males, especially elderly males. Second only to lung cancer, prostate cancer has a 15% incidence rate and is expected to cause more than 800000 deaths per year in 2024[1,2]. Albertsen et al[3] recently reported a mortality rate of 3.3% in the first 15 years of follow-up after conservative treatment of PCa patients with few comorbidities. Currently, some of the leading drugs and methods for treating PCa include docetaxel, cabazitaxel, abiraterone acetate, radium-223 therapy, sipuleucel-T, and surgery[4]. Due to the remarkable androgen-dependent nature of PCa, androgen blockade therapy is an effective treatment for advanced PCa and is a major cause of death in patients who eventually develop hormone-resistant PCa[5]. Therefore, the development of an effective treatment for PCa is crucial. Clinical trials have shown that traditional Chinese medicine has several unique advantages in the treatment of PCa, and many compounds isolated from traditional Chinese medicines also exhibit distinct anti-PCa activity[6]. The advantages of traditional Chinese medicine include low toxicity, few side effects, prevention of tumour occurrence, enhancement of therapeutic effects, and reduction in the recurrence rate[7]. Many components of Chinese medicine, such as andrographolide, evodiamine, guttiferone F, honokiol and isorhapontigenin, have obvious anticancer activity[6]. Studies have shown that the use of traditional Chinese medicine can significantly improve the survival rate of PCa patients[8-10]. Coridius chinensis (Cc) is a type of Chinese medicine that is effective against liver cancer, stomach cancer, and breast cancer[11-13]. Cc blocks the liver cancer cell cycle and promotes apoptosis, and tumour growth is inhibited in animals[11]. Chen et al[12] demonstrated that the active peptide from Cc inhibited cell proliferation in stomach cancer cells, but the underlying mechanism has not been demonstrated. In addition, the most active component has been shown to have an anticancer effect, but the underlying mechanisms are not yet clear[14]. In this study, network pharmacology and molecular docking technology were used to explore the potential of Cc to treat PCa. The molecular docking results verified that the core active compounds were associated with Cc and key targets associated with PCa, providing a scientifically sound basis for further elucidation of the mechanisms of action of these drug components and disease-related targets. Figure 1 shows the flow chart of the anti-PCa analysis of the components of Cc via network pharmacology and molecular docking technology.

Open in New Tab   Full Size Figure   Download Figure

Figure 1 A schematic diagram of the study on Coridius chinensis as an anti-prostate cancer treatment. Network pharmacology was used to filter the compounds of Coridius chinensis for the treatment of prostate cancer; after 63 molecular docking studies, four bioactive compounds were found to bind tightly with candidate molecules.

Cc has been widely applied in the treatment of cancer in the clinic. As several studies have shown, Cc induces antitumorigenic effects and could be used as a novel therapeutic option for metastatic breast cancer and gastric cancer[13,14]. However, whether Cc can be used to treat PCa and the underlying mechanisms are still unclear.

Based on earlier studies, the bioactive ingredients in Cc, including asponguanosines A, asponguanine B, asponguanine C, aspongpyrazine A, N-acetyldopamine, aspongadenine B, and aspongpyrazine B, have not been fully characterized or assessed in animal experiments. Among them, asponguanine B has better biological activity, but only in terms of stimulating the proliferation of neural stem cells[16,17].

By analysis of the PPI network, our study revealed that the core targets were EGFR, MMP9, PTGS2, SIRT1, NOS3, ICAM1, PPARG, MMP2 and ACE. EGFR is expressed in 100% of hormone-refractory PCa metastases, which indicates that this receptor is the main transduction pathway for tumour growth[27]. The progression of PCa can be inhibited by regulating the expression of cathepsin B and MMP9 in three PCa cell lines[28]. SIRT1 is highly expressed in PCa in multiple human PCa cell lines and in a prostate-specific PTEN knockout mouse model[29]. The Glu298Asp polymorphism in the NOS3 gene has been implicated as a risk factor for PCa[30]. The main pathways identified by KEGG analysis were pathways in cancer, the PI3K-Akt signalling pathway, neuroactive ligand-receptor interaction, chemical carcinogenesis-receptor activation and the MAPK signalling pathway. There were 17 enriched pathways involving EGFR, such as the PI3K-Akt signalling pathway and EGFR tyrosine kinase inhibitor resistance. There were 8 pathways related to MMP9, such as pathways in cancer and PCa, and 10 pathways related to MMP9, such as the VEGF signalling pathway and arachidonic acid metabolism.

Molecular docking analysis showed that the 7 key bioactive components had a certain binding activity with 9 representative targets based on the above study results (Table 1). A total of 71% of the interactions among these components and targets had a binding energy lower than -6 kcal/mol, which indicated that the potential efficacy of Cc against PCa is great. The docking results showed that the two compounds asponguanosines A and aspongpyrazine A could bind the targets well, and the docking results also showed that asponguanosines A bound to MMP2 with the highest binding energy (-8.7 kcal/mol), indicating that this interaction was the most stable. In addition, aspongpyrazine A bonding to MMP9, aspongpyrazine A bonding to NOS3 and asponguanosines A bonding to SIRT1 also showed great potential effects against PCa, with binding energies lower than -8 kcal/mol and two or more hydrogen bonds.

The present study still has several limitations. We employed only a bioinformatics approach to investigate the effects of Cc on PCa. Although we identified multiple important bioactive components of CC for the treatment of PCa in the present study, these compounds are not fully representative of Cc. Therefore, there is a need to consider molecular biological approaches to further validate our findings. Furthermore, because the effects and mechanisms of other potentially active compounds on PCa have not yet been explained and validated, further research is needed.

The results of this study indicated that Cc has multiple active ingredients that exert anti-PCa effects. Aspongpyrazine A and asponguanosines A of Cc had high binding affinities for representative targets, indicating that they may be the most promising PCa-targeting drugs in terms of their drug binding capacity; however, more studies are needed. The proteins EGFR, MMP9, ICAM1, PPARG, MMP2 and ACE are potential therapeutic targets of Cc for the treatment of PCa. The experimental data of this study provide a theoretical basis for the development of anti-PCa drugs. However, the anti-PCa effects of the two components of Cc still need to be verified in additional in vitro and in vivo experiments. Our study may provide some direction for the treatment of PCa.