https://scholars.lib.ntu.edu.tw/handle/123456789/634496
Title: | Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells | Authors: | Hsu, Ya-Fen FAN-LU KUNG Huang, Tzu-En Deng, Yi-Ning JIH-HWA GUH Marchetti, Paolo Marchesi, Elena Perrone, Daniela Navacchia, Maria Luisa LIH-CHING HSU |
Keywords: | anticancer; apoptosis; autophagy; bile acid–dihydroartemisinin hybrids; hepatocellular carcinoma; oxidative stress | Issue Date: | 3-Mar-2023 | Journal Volume: | 28 | Journal Issue: | 5 | Start page/Pages: | 2358 | Source: | Molecules (Basel, Switzerland) | Abstract: | Hepatocellular carcinoma is the third most common cause of cancer-related death according to the International Agency for Research on Cancer. Dihydroartemisinin (DHA), an antimalarial drug, has been reported to exhibit anticancer activity but with a short half-life. We synthesized a series of bile acid-dihydroartemisinin hybrids to improve its stability and anticancer activity and demonstrated that an ursodeoxycholic-DHA (UDC-DHA) hybrid was 10-fold more potent than DHA against HepG2 hepatocellular carcinoma cells. The objectives of this study were to evaluate the anticancer activity and investigate the molecular mechanisms of UDCMe-Z-DHA, a hybrid of ursodeoxycholic acid methyl ester and DHA via a triazole linkage. We found that UDCMe-Z-DHA was even more potent than UDC-DHA in HepG2 cells with IC50 of 1 μM. Time course experiments and stability in medium determined by cell viability assay as well as HPLC-MS/MS analysis revealed that UDCMe-Z-DHA was more stable than DHA, which in part accounted for the increased anticancer activity. Mechanistic studies revealed that UDCMe-Z-DHA caused G0/G1 arrest and induced reactive oxygen species (ROS), mitochondrial membrane potential loss and autophagy, which may in turn lead to apoptosis. Compared to DHA, UDCMe-Z-DHA displayed much lower cytotoxicity toward normal cells. Thus, UDCMe-Z-DHA may be a potential drug candidate for hepatocellular carcinoma. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/634496 | ISSN: | 1420-3049 | DOI: | 10.3390/molecules28052358 |
Appears in Collections: | 藥學系 |
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