Anticancer Activity and Molecular Mechanisms of an Ursodeoxycholic Acid Methyl Ester-Dihydroartemisinin Hybrid via a Triazole Linkage in Hepatocellular Carcinoma Cells

  • Molecules. 2023 Mar 3;28(5):2358. doi: 10.3390/molecules28052358.
Ya-Fen Hsu  1 ,  Fan-Lu Kung  1 ,  Tzu-En Huang  1 ,  Yi-Ning Deng  1 ,  Jih-Hwa Guh  1 ,  Paolo Marchetti  2 ,  Elena Marchesi  3 ,  Daniela Perrone  3 ,  Maria Luisa Navacchia  4 ,  Lih-Ching Hsu  1
Affiliations
  • 1. School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan.
  • 2. Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy.
  • 3. Department of Environmental and Prevention Sciences, University of Ferrara, 44121 Ferrara, Italy.
  • 4. Institute for Organic Synthesis and Photoreactivity (ISOF), National Research Council of Italy (CNR), 44129 Bologna, Italy.
PMID: 36903603 DOI: 10.3390/molecules28052358
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.

Keywords
anticancer; apoptosis; autophagy; bile acid–dihydroartemisinin hybrids; hepatocellular carcinoma; oxidative stress.
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