Abstract
Background: 2-Dodecyl-6-Methoxycyclohexa-2, 5-Diene-1,4-Dione (DMDD) was purified from the roots of Averrhoa carambola L. Previous research demonstrated that DMDD is a small molecular compound with significant therapeutic potential for tumors. However, the potential targets and pharmacological mechanism of DMDD to treat lung cancer has not been reported. Methods: We employed network pharmacology and experimental evaluation to reveal the pharmacological mechanism of DMDD against lung cancer. Potential therapeutic targets of DMDD were screened by PharmMapper. Differentially expressed genes (DEGs) in The Cancer Genome Atlas (TCGA) lung cancer data sets were extracted and analyzed by GEPIA2. The mechanism of DMDD against lung cancer was determined by PPI, gene ontology (GO) and KEGG pathway enrichment analysis. Survival analysis and molecular docking were employed to obtain the key targets of DMDD. Human lung cancer cell lines H1975 and PC9 were used to detect effects of DMDD treatment in vitro. The expression of key targets after DMDD treated was validated by Western Blot. Results: A total of 60 Homo sapiens potential therapeutic targets of DMDD and 3,545 DEGs in TCGA lung cancer datasets were identified. Gene ontology and pathway analysis revealed characteristic of the potential targets of DMDD and DEGs in lung cancer respectively. Cell cycle and pathways in cancer were overlapping with DMDD potential targets and lung cancer DEGs. Eight overlapping genes were found between DMDD potential therapeutic targets and lung cancer related DEGs. Survival analysis showed that high expression of DMDD potential targets CCNE1 and E2F1 was significantly related to poor patient survival in lung cancer. Molecular docking found that DMDD exhibited significant binding affinities within the active site of CCNE1 and E2F1. Further tests showed that DMDD inhibited the proliferation, migration and clone formation in lung cancer cell lines (H1975 and PC9) in a dose and time dependent manner. Mechanistically, DMDD treatment decreased the expression of CDK2, CCNE1, E2F1 proteins and induced cell cycle arrest at the G1/S phase in H1975 and PC9 cells. Conclusion: These results delineated that DMDD holds therapeutic potential that blocks tumorigenesis by cell cycle regulation in lung cancer, and may provide potential therapies for lung cancer.
Highlights
Lung cancer is the most frequently diagnosed and leading cause of cancer-related deaths globally (Siegel et al, 2020), with the most common subtypes being adenocarcinomas (AD) and squamous cell carcinomas (SCC) (Youlden et al, 2008)
We found that DMDD could enter into the N-terminal cyclin box of CCNE1 (PDB code: 1W98) which leads to pCDK2 kinase activation (Honda et al, 2005), and stayed in the binding pocket surrounded by key residues (His147, Ile345, Val337 and Lys145) (Figure 4A)
Previous clinical studies showed that CCNE1 and E2F1 have a tumor promoting effect in many cancers including lung cancer (Salon et al, 2007; Garcia-Martinez et al, 2020). These results suggest that DMDD potential targets CCNE1, E2F1 are involved in the development of various cancers and are closely related to cell cycle and tumorigenesis in lung cancer
Summary
Lung cancer is the most frequently diagnosed and leading cause of cancer-related deaths globally (Siegel et al, 2020), with the most common subtypes being adenocarcinomas (AD) and squamous cell carcinomas (SCC) (Youlden et al, 2008). Since there were no obvious clinical symptoms or only mild symptoms in the early stage of lung cancer, nearly 60–80% lung cancer patients were in the advanced stage when the diagnosis was confirmed and missed the best time for surgery (Motoi et al, 2008; Scagliotti et al, 2008; Kowalczyk and Jassem, 2020). The first-line chemotherapy for lung carcinoma treatment is platinum-based drugs combined with third-generation chemotherapy drugs (Scagliotti et al, 2008; Li et al, 2020; Yao et al, 2020). Because of serious side effect and multi-drug resistance, many patients with lung cancer are forced to stop drug treatment. There is an urgent need for new, effective, safe and low toxic antitumor drugs for lung cancer
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