School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan.
Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy.
Molecules. 2023 Mar 3;28(5):2358. doi: 10.3390/molecules28052358.
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 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.
根据国际癌症研究机构的数据，肝细胞癌是癌症相关死亡的第三大常见原因。青蒿素（DHA）是一种抗疟药物，据报道具有抗癌活性，但半衰期短。我们合成了一系列胆酸-青蒿素杂合体，以提高其稳定性和抗癌活性，并证明熊去氧胆酸-DHA（UDC-DHA）杂合体对 HepG2 肝癌细胞的活性比 DHA 高 10 倍。本研究的目的是评估 UDCMe-Z-DHA 的抗癌活性，并探讨其分子机制，UDCMe-Z-DHA 是通过三唑键将熊去氧胆酸甲酯和 DHA 连接而成的杂合体。我们发现 UDCMe-Z-DHA 在 HepG2 细胞中的活性比 UDC-DHA 更强，IC 为 1 μM。细胞活力测定的时程实验和稳定性以及 HPLC-MS/MS 分析表明，UDCMe-Z-DHA 比 DHA 更稳定，这在一定程度上解释了其抗癌活性的增强。机制研究表明，UDCMe-Z-DHA 导致 G0/G1 期阻滞，并诱导活性氧（ROS）、线粒体膜电位丧失和自噬，进而导致细胞凋亡。与 DHA 相比，UDCMe-Z-DHA 对正常细胞的细胞毒性要低得多。因此，UDCMe-Z-DHA 可能是肝细胞癌的潜在药物候选物。
