Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells

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. Dihydroarte...

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Autores principales:	Tzu-En Huang, Yi-Ning Deng, Jui-Ling Hsu, Wohn-Jenn Leu, Elena Marchesi, Massimo L. Capobianco, Paolo Marchetti, Maria Luisa Navacchia, Jih-Hwa Guh, Daniela Perrone, Lih-Ching Hsu
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2020
Materias:	hepatocellular carcinoma bile acid-dihydroartemisinin hybrid G0/G1 arrest apoptosis reactive oxygen species mitochondrial membrane potential loss Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/311890ab56b4453cad17527f699ccc44
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spelling	oai:doaj.org-article:311890ab56b4453cad17527f699ccc442021-11-05T16:52:15ZEvaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells1663-981210.3389/fphar.2020.599067https://doaj.org/article/311890ab56b4453cad17527f699ccc442020-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2020.599067/fullhttps://doaj.org/toc/1663-9812Hepatocellular 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 IC50 of 2.16 μM, which was 18.5-fold better than DHA with an IC50 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.Tzu-En HuangYi-Ning DengJui-Ling HsuWohn-Jenn LeuElena MarchesiMassimo L. CapobiancoPaolo MarchettiMaria Luisa NavacchiaJih-Hwa GuhDaniela PerroneLih-Ching HsuFrontiers Media S.A.articlehepatocellular carcinomabile acid-dihydroartemisinin hybridG0/G1 arrestapoptosisreactive oxygen speciesmitochondrial membrane potential lossTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 11 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	hepatocellular carcinoma bile acid-dihydroartemisinin hybrid G0/G1 arrest apoptosis reactive oxygen species mitochondrial membrane potential loss Therapeutics. Pharmacology RM1-950
spellingShingle	hepatocellular carcinoma bile acid-dihydroartemisinin hybrid G0/G1 arrest apoptosis reactive oxygen species mitochondrial membrane potential loss Therapeutics. Pharmacology RM1-950 Tzu-En Huang Yi-Ning Deng Jui-Ling Hsu Wohn-Jenn Leu Elena Marchesi Massimo L. Capobianco Paolo Marchetti Maria Luisa Navacchia Jih-Hwa Guh Daniela Perrone Lih-Ching Hsu Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells
description	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 IC50 of 2.16 μM, which was 18.5-fold better than DHA with an IC50 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.
format	article
author	Tzu-En Huang Yi-Ning Deng Jui-Ling Hsu Wohn-Jenn Leu Elena Marchesi Massimo L. Capobianco Paolo Marchetti Maria Luisa Navacchia Jih-Hwa Guh Daniela Perrone Lih-Ching Hsu
author_facet	Tzu-En Huang Yi-Ning Deng Jui-Ling Hsu Wohn-Jenn Leu Elena Marchesi Massimo L. Capobianco Paolo Marchetti Maria Luisa Navacchia Jih-Hwa Guh Daniela Perrone Lih-Ching Hsu
author_sort	Tzu-En Huang
title	Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells
title_short	Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells
title_full	Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells
title_fullStr	Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells
title_full_unstemmed	Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells
title_sort	evaluation of the anticancer activity of a bile acid-dihydroartemisinin hybrid ursodeoxycholic-dihydroartemisinin in hepatocellular carcinoma cells
publisher	Frontiers Media S.A.
publishDate	2020
url	https://doaj.org/article/311890ab56b4453cad17527f699ccc44
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Evaluation of the Anticancer Activity of a Bile Acid-Dihydroartemisinin Hybrid Ursodeoxycholic-Dihydroartemisinin in Hepatocellular Carcinoma Cells

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