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Phytother Res. 2019 Mar 19. doi: 10.1002/ptr.6329. [Epub ahead of print]

Morin enhances auranofin anticancer activity by up-regulation of DR4 and DR5 and modulation of Bcl-2 through reactive oxygen species generation in Hep3B human hepatocellular carcinoma cells.

Author information

1
Department of Biochemistry, Dongeui University College of Korean Medicine and Anti-Aging Research Center, Dongeui University, Busan, South Korea.
2
Department of Molecular Biology, Pusan National University, Busan, South Korea.
3
Department of Internal Medicine, Institute of Health Sciences, and Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, South Korea.
4
Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, South Korea.
5
Department of Molecular Biology, Dongeui University, Busan, Republic of Korea.
6
Department of Surgery, Konkuk University School of Medicine, Seoul, South Korea.
7
Department of Biological Science, Dong-A University, Busan, South Korea.
8
Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, South Korea.
9
Department of Immunology, School of Medicine, Keimyung University, Daegu, South Korea.
10
School of Veterinary Medicine, Research Institute of Life Science, Gyeongsang National University, Jinju, South Korea.
11
Department of Neurosurgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Republic of Korea.
12
Department of Chemistry, Research Institute of Life Science, Gyeongsang National University, Jinju, South Korea.
13
Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, South Korea.

Abstract

Evidence suggests that auranofin (AF) exhibits anticancer activity by inhibiting thioredoxin reductase (TrxR). Here, in this study, we have investigated the synergistic effects of AF and morin and their mechanism for the anticancer effects focusing on apoptosis in Hep3B human hepatocellular carcinoma cells. We assessed the anticancer activities by annexin V/PI double staining, caspase, and TrxR activity assay. Morin enhances the inhibitory effects on TrxR activity of AF as well as reducing cell viability. Annexin V/PI double staining revealed that morin/AF cotreatment induced apoptotic cell death. Morin enhances AF-induced mitochondrial membrane potential (ΔΨm) loss and cytochrome c release. Further, morin/AF cotreatment upregulated death receptor DR4/DR5, modulated Bcl-2 family members (upregulation of Bax and downregulation of Bcl-2), and activated caspase-3, -8, and -9. Morin also enhances AF-induced reactive oxygen species (ROS) generation. The anticancer effects results from caspase-dependent apoptosis, which was triggered via extrinsic pathway by upregulating TRAIL receptors (DR4/DR5) and enhanced via intrinsic pathway by modulating Bcl-2 and inhibitor of apoptosis protein family members. These are related to ROS generation. In conclusion, this study provides evidence that morin can enhance the anticancer activity of AF in Hep3B human hepatocellular carcinoma cells, indicating that its combination could be an alternative treatment strategy for the hepatocellular carcinoma.

KEYWORDS:

Hep3B cells; ROS; apoptosis; auranofin; cancer; morin

PMID:
30887612
DOI:
10.1002/ptr.6329

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