Network pharmacology, molecular docking and experimental study of CEP in nasopharyngeal carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: The Stephania cephalantha Hayata is an important traditional medicinal plant widely used in traditional medicine to treat cancer. Cepharanthine (CEP) was extracted from the roots of Stephania cephalantha Hayata. It has been found to exhibit anticancer activity in different types of cancer cells. Nevertheless, the activity of CEP against nasopharyngeal carcinoma (NPC) and its underlying mechanism warrant further investigation. AIMS OF THE STUDY: NPC is an invasive and highly metastatic malignancy that affects the head and neck region. This research aimed to investigate the pharmacological properties and underlying mechanism of CEP against NPC, aiming to offer novel perspectives on treating NPC using CEP. MATERIALS AND METHODS: In vitro, the pharmacological activity of CEP against NPC was evaluated using the CCK-8 assay. To predict and elucidate the anticancer mechanism of CEP against NPC, we employed network pharmacology, conducted molecular docking analysis, and performed Western blot experiments. In vivo validation was performed through a nude mice xenograft model of human NPC, Western blot and immunohistochemical (IHC) assays to confirm pharmacological activity and the mechanism. RESULTS: In a dose-dependent manner, the proliferation and clonogenic capacity of NPC cells were significantly inhibited by CEP. Additionally, NPC cell migration was suppressed by CEP. The results obtained from network pharmacology experiments revealed that anti-NPC effect of CEP was associated with 8 core targets, including EGFR, AKT1, PIK3CA, and mTOR. By performing molecular docking, the binding capacity of CEP to the candidate core proteins (EGFR, AKT1, PIK3CA, and mTOR) was predicted, resulting in docking energies of -10.0 kcal/mol for EGFR, -12.4 kcal/mol for PIK3CA, -10.8 kcal/mol for AKT1, and -8.6 kcal/mol for mTOR. The Western blot analysis showed that CEP effectively suppressed the expression of EGFR and the phosphorylation levels of downstream signaling proteins, including PI3K, AKT, mTOR, and ERK. After CEP intervention, a noteworthy decrease in tumor size, without inducing any toxicity, was observed in NPC xenograft nude mice undergoing in vivo treatment. Additionally, IHC analysis demonstrated a significant reduction in the expression levels of EGFR and Ki-67 following CEP treatment. CONCLUSION: CEP exhibits significant pharmacological effects on NPC, and its mechanistic action involves restraining the activation of the EGFR/PI3K/AKT pathway. CEP represents a promising pharmaceutical agent for addressing and mitigating NPC.

Gambogic acid suppresses nasopharyngeal carcinoma via rewiring molecular network of cancer malignancy and immunosurveillance.

Nasopharyngeal carcinoma (NPC) is a malignant tumor highly prevalent in Southeast Asia. The distant metastasis and disease recurrence are still unsolved clinical problems. In recent years, traditional Chinese medicine (TCM) monomers have become significantly attractive due to their advantages. Using high throughput drug sensitivity screening, we identified gambogic acid (GA) as a common TCM monomer displaying multiple anti-NPC effects. GA could effectively inhibit the proliferation of low differentiated cells and highly metastatic cells in NPC via inducing apoptosis and G2/M cell cycle arrest. In addition, GA obviously repressed the abilities of cell clone, migration, invasion, angiogenesis and represented satisfied synergistic effects combined with chemotherapy. Importantly, we found the elevated immune checkpoint CD47 stimulated after chemotherapy was dramatically impaired by GA treatment. Mechanically, the network pharmacology analyses unraveled that the oncogenic signaling pathways including STATs were rewired by GA treatment. Taken together, our study reveals a molecular basis and provides a rationale for GA application as the treatment regime in NPC therapy in future.