Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells
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 a...
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MDPI AG
2023-03-01
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| Online Access: | https://www.mdpi.com/1420-3049/28/5/2358 |
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| author | Ya-Fen Hsu Fan-Lu Kung Tzu-En Huang Yi-Ning Deng Jih-Hwa Guh Paolo Marchetti Elena Marchesi Daniela Perrone Maria Luisa Navacchia Lih-Ching Hsu |
| author_facet | Ya-Fen Hsu Fan-Lu Kung Tzu-En Huang Yi-Ning Deng Jih-Hwa Guh Paolo Marchetti Elena Marchesi Daniela Perrone Maria Luisa Navacchia Lih-Ching Hsu |
| author_sort | Ya-Fen Hsu |
| collection | DOAJ |
| description | 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 IC<sub>50</sub> 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. |
| first_indexed | 2024-03-11T07:17:11Z |
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| language | English |
| last_indexed | 2024-03-11T07:17:11Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-ff24007f53004f1a8586ea1f00420e9a2023-11-17T08:15:35ZengMDPI AGMolecules1420-30492023-03-01285235810.3390/molecules28052358Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma CellsYa-Fen Hsu0Fan-Lu Kung1Tzu-En Huang2Yi-Ning Deng3Jih-Hwa Guh4Paolo Marchetti5Elena Marchesi6Daniela Perrone7Maria Luisa Navacchia8Lih-Ching Hsu9School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanSchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanDepartment of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, ItalyDepartment of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, ItalyInstitute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), 44129 Bologna, ItalySchool of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, TaiwanHepatocellular 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 IC<sub>50</sub> 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.https://www.mdpi.com/1420-3049/28/5/2358hepatocellular carcinomabile acid–dihydroartemisinin hybridsanticanceroxidative stressautophagyapoptosis |
| spellingShingle | Ya-Fen Hsu Fan-Lu Kung Tzu-En Huang Yi-Ning Deng Jih-Hwa Guh Paolo Marchetti Elena Marchesi Daniela Perrone Maria Luisa Navacchia Lih-Ching Hsu Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells Molecules hepatocellular carcinoma bile acid–dihydroartemisinin hybrids anticancer oxidative stress autophagy apoptosis |
| title | Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells |
| title_full | Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells |
| title_fullStr | Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells |
| title_full_unstemmed | Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells |
| title_short | Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells |
| title_sort | anticancer activity and molecular mechanisms of an ursodeoxycholic acid methyl ester dihydroartemisinin hybrid via a triazole linkage in hepatocellular carcinoma cells |
| topic | hepatocellular carcinoma bile acid–dihydroartemisinin hybrids anticancer oxidative stress autophagy apoptosis |
| url | https://www.mdpi.com/1420-3049/28/5/2358 |
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