Fisheries and Aquatic Sciences

The Korean Society of Fisheries and Aquatic Science (한국수산과학회)
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Auranofin accelerates spermidine-induced apoptosis via reactive oxygen species generation and suppression of PI3K/Akt signaling pathway in hepatocellular carcinoma

  • Hyun Hwangbo (Korea Nanobiotechnology Center, Pusan National University) ;
  • Da Hye Kim (Department of Biochemistry, Dong-Eui University College of Korean Medicine) ;
  • Min Yeong Kim (Department of Biochemistry, Dong-Eui University College of Korean Medicine) ;
  • Seon Yeong Ji (Department of Biochemistry, Dong-Eui University College of Korean Medicine) ;
  • EunJin Bang (Department of Biochemistry, Dong-Eui University College of Korean Medicine) ;
  • Su Hyun Hong (Department of Biochemistry, Dong-Eui University College of Korean Medicine) ;
  • Yung Hyun Choi (Department of Biochemistry, Dong-Eui University College of Korean Medicine) ;
  • JaeHun Cheong (Korea Nanobiotechnology Center, Pusan National University)
  • Received : 2023.01.02
  • Accepted : 2023.01.18
  • Published : 2023.02.28
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Abstract

Auranofin is a US Food and Drug Administration (FDA)-approved anti-arthritis medication that functions as a thioredoxin reductase inhibitor. Spermidine, a polyamine present in marine algae, can exert various physiological functions. Herein, we examined the synergistic anticancer activity of auranofin and spermidine in hepatocellular carcinoma (HCC). Combined treatment with auranofin and spermidine suppressed cell viability more efficiently than either treatment alone in HCC Hep3B cells. The isobologram plotted by calculating the half maximal inhibitory concentration (IC50) values of each drug indicated that the two drugs exhibited a synergistic effect. Based on the analysis of annexin V and cell cycle distribution, auranofin and spermidine markedly induced apoptosis in Hep3B cells. Moreover, auranofin and spermidine increased mitochondria-mediated apoptosis by promoting mitochondrial membrane potential (Δψm) loss. Auranofin and spermidine significantly increased reactive oxygen species (ROS) production in Hep3B cells, and the blocking ROS suppressed apoptosis induced by spermidine and auranofin. In addition, auranofin and spermidine reduced the expression of phosphorylated phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt), and PI3K inhibitor accelerated auranofin- and spermidine-induced apoptosis. Using ROS scavenger and PI3K inhibitor, we revealed that ROS acts upstream of auranofin- and spermidine-induced apoptosis. Collectively, our study suggests that combination treatment with auranofin and spermidine could afford synergistic anticancer activity via ROS overproduction and reduced PI3K/Akt signaling pathway.

Keywords

Acknowledgement

This study was financially supported by the 2021 Post-Doc. Development Program of Pusan National University and Korea Institute of Marine Science & Technology Promotion (KIMST) funded by the Ministry of Oceans and Fisheries (20220488).

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