| Summary: | 碩士 === 高雄醫學大學 === 天然藥物研究所 === 97 === Malignant neoplasm has become the leading cause of death in Taiwan. According to stastistic data from Department of Health, hepatocellular carcinoma (HCC) is the second common cancer in Taiwan. At present, systemic therapies including chemotherapy and molecular targeted therapy can not effectively treat this malignancy because of resistance to drugs and descent of tolerance caused by liver dysfunction. Therefore, it is an emergent task to find new drug candidates for treating HCC.
Natural products represent a rich source of new chemical compounds for developing anticancer drugs. In previous studies, squamocin, an Annonaceous acetogenin, has been reported as a potential anticancer agent. In the present study, we found that squamocin inhibited the growth of HepG2 cells at very low concentrations (0.5~5nM). Flow cytometry showed that squamocin induced cell cycle arrest at G1 and G2/M phase in HepG2 cells. Western blotting revealed that squamocin decreased the expression of cyclin D, Cdk2 and Cdk4. Besides, squamocin treatment also led to an increase in hypophosphorylated pRB and a decrease in E2F1 protein levels. In G2 phase-related proteins, squamoicin decrease Cdk1 and Cdc25C and induced Cdc25C Ser216 phosphorylation. To analysis the upstream regulators of Cdc25C, we observed the activation of Chk1, Chk2, and p38 after treatment of HepG2 cells with squamocin. The results suggested Chk1, Chk2 and p38 might be responsible for squamocin-induced Cdc25C downregulation and thus led to cell cycle arrest in G2/M phase. In addition, prolonged treatment (48h) of HepG2 cells with a high concentration of squamocin (5nM) induced apoptotic death. However, squamocin did not activate caspase cascade, suggesting that squamocin-induced apoptosis is caspase-independent.
In conclusion, based on its very potent and novel activity, squamocin can be considered as a promising anticancer drug, and it is worthy to find the special target of squamocin in HepG2 cells.
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