Huang Tzu-En, Deng Yi-Ning, Hsu Jui-Ling, Leu Wohn-Jenn, Marchesi Elena, Capobianco Massimo L, Marchetti Paolo, Navacchia Maria Luisa, Guh Jih-Hwa, Perrone Daniela, Hsu Lih-Ching
School of Pharmacy, National Taiwan University, Taipei, Taiwan.
Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
Front Pharmacol. 2020 Nov 10;11:599067. doi: 10.3389/fphar.2020.599067. eCollection 2020.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy in adults and accounts for 85-90% of all primary liver cancer. Based on the estimation by the International Agency for Research on Cancer in 2018, liver cancer is the fourth leading cause of cancer death globally. Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is a well-known drug for the treatment of malaria. Previous studies have demonstrated that DHA exhibits antitumor effects toward a variety of human cancers and has a potential for repurposing as an anticancer drug. However, its short half-life is a concern and may limit the application in cancer therapy. We have reported that UDC-DHA, a hybrid of bile acid ursodeoxycholic acid (UDCA) and DHA, is ∼12 times more potent than DHA against a HCC cell line HepG2. In this study, we found that UDC-DHA was also effective against another HCC cell line Huh-7 with an IC of 2.16 μM, which was 18.5-fold better than DHA with an IC of 39.96 μM. UDC-DHA was much more potent than the combination of DHA and UDCA at 1:1 molar ratio, suggesting that the covalent linkage rather than a synergism between UDCA and DHA is critical for enhancing DHA potency in HepG2 cells. Importantly, UDC-DHA was much less toxic to normal cells than DHA. UDC-DHA induced G0/G1 arrest and apoptosis. Both DHA and UDC-DHA significantly elevated cellular reactive oxygen species generation but with different magnitude and timing in HepG2 cells; whereas only DHA but not UDC-DHA induced reactive oxygen species in Huh-7 cells. Depolarization of mitochondrial membrane potential was detected in both HepG2 and Huh-7 cells and may contribute to the anticancer effect of DHA and UDC-DHA. Furthermore, UDC-DHA was much more stable than DHA based on activity assays and high performance liquid chromatography-MS/MS analysis. In conclusion, UDC-DHA and DHA may exert anticancer actions via similar mechanisms but a much lower concentration of UDC-DHA was required, which could be attributed to a better stability of UDC-DHA. Thus, UDC-DHA could be a better drug candidate than DHA against HCC and further investigation is warranted.
肝细胞癌（HCC）是成人中最常见的原发性肝脏恶性肿瘤，占所有原发性肝癌的85 - 90%。根据国际癌症研究机构2018年的估计，肝癌是全球第四大致癌死亡原因。双氢青蒿素（DHA）是青蒿素衍生物的主要活性代谢产物，是一种治疗疟疾的知名药物。先前的研究表明，DHA对多种人类癌症具有抗肿瘤作用，并且有作为抗癌药物重新利用的潜力。然而，其半衰期短是一个问题，可能会限制其在癌症治疗中的应用。我们曾报道，熊去氧胆酸（UDCA）与DHA的杂合物UDC - DHA对肝癌细胞系HepG2的活性比DHA高约12倍。在本研究中，我们发现UDC - DHA对另一种肝癌细胞系Huh - 7也有效，其半数抑制浓度（IC）为2.16 μM，比DHA的IC（39.96 μM）高18.5倍。UDC - DHA比1:1摩尔比的DHA与UDCA组合的活性要强得多，这表明UDCA与DHA之间的共价连接而非协同作用对于增强DHA在HepG2细胞中的活性至关重要。重要的是，UDC - DHA对正常细胞的毒性比DHA小得多。UDC - DHA诱导G0/G1期阻滞和细胞凋亡。DHA和UDC - DHA均显著提高HepG2细胞中细胞活性氧的产生，但程度和时间不同；而在Huh - 7细胞中，只有DHA而非UDC - DHA诱导活性氧产生。在HepG2和Huh - 7细胞中均检测到线粒体膜电位的去极化，这可能有助于DHA和UDC - DHA的抗癌作用。此外，基于活性测定和高效液相色谱 - 质谱/质谱分析，UDC - DHA比DHA稳定得多。总之，UDC - DHA和DHA可能通过相似的机制发挥抗癌作用，但UDC - DHA所需的浓度要低得多，这可能归因于UDC - DHA更好的稳定性。因此，UDC - DHA可能是比DHA更好的抗肝癌候选药物，值得进一步研究。
