Evaluation of anticancer activity of bile acid-dihydroartemisinin hybrids in hepatocellular carcinoma cells
| Autor: | Tzu-En Huang, 黃子恩 |
|---|---|
| Rok vydání: | 2019 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 107 Hepatocellular carcinoma (HCC) is the most common primary liver malignancy in adults and accounts for up to 90% of all primary liver cancer. Based on the data estimated by the International Agency for Research on Cancer (IARC) in 2018, liver cancer is the fourth common cause of cancer death overall in the world. Dihydroartemisinin (DHA), a main active metabolite of artemisinin derivatives, is a well-known drug used in the treatment against malaria. In previous studies, DHA has been demonstrated to exhibit antitumor effects toward a wide range of human cancers. In order to improve the cytotoxic effect against cancer cells, a series of bile acid-dihydroartemisinin (BA-DHA) hybrids were synthesized. Among them, UDC-DHA (#12) is the most potent anticancer compound against HCC cells with IC50 values of 1.75 μM (HepG2 cells) and 2.16 μM (Huh-7 cells). Moreover, UDC-DHA (#12) is more potent than the combination of DHA (#1) and UDCA (#2) at 1:1 molar ratio. In this study, the mechanism of action of UDC DHA (#12) was also investigated. The propidium iodide (PI) staining and flow cytometric analysis demonstrated that UDC DHA (#12) significantly induced G0/G1 arrest and further induced subG1 populations, which represent the apoptotic cells. Apoptotic markers including cleaved caspase-9, caspase-3, and cleaved PARP were significantly induced by UDC DHA (#12) in HepG2 cells. Interestingly, the 2′,7′ Dichlorofluorescin diacetate (DCFH DA) assay demonstrated that DHA (#1) and UDC DHA (#12) significantly elevated cellular reactive oxygen species (ROS) levels over time and the ROS levels peaked at 12 h and 24 h, respectively. Furthermore, our results indicated that both induction of ROS and depolarization of mitochondrial membrane potential (MMP), which could be reversed by an antioxidant N acetylcysteine (NAC), contributed to the anticancer effect of UDC DHA (#12). In conclusion, UDC-DHA (#12) could be a drug candidate against HCC and further investigation of the detailed mechanism is warranted. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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