Fisheries and Aquatic Sciences

한국수산과학회 (The Korean Society of Fisheries and Aquatic Science)
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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)
  • 투고 : 2023.01.02
  • 심사 : 2023.01.18
  • 발행 : 2023.02.28
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초록

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.

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과제정보

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).

참고문헌

  1. Abdalbari FH, Telleria CM. The gold complex auranofin: new perspectives for cancer therapy. Discov Oncol. 2021;12:42.
  2. Chakraborty E, Sarkar D. Emerging therapies for hepato-cellular carcinoma (HCC). Cancers. 2022;14:2798.
  3. Chen S, Cao Q, Wen W, Wang H. Targeted therapy for hepatocellular carcinoma: challenges and opportunities. Cancer Lett. 2019;460:1-9. https://doi.org/10.1016/j.canlet.2019.114428
  4. Cohen GM. Caspases: the executioners of apoptosis. Biochem J. 1997;326:1-16. https://doi.org/10.1042/bj3260001
  5. Cucarull B, Tutusaus A, Rider P, Hernaez-Alsina T, Cuno C, Garcia de Frutos P, et al. Hepatocellular carcinoma: molecular pathogenesis and therapeutic advances. Cancers. 2022;14:621.
  6. Cui XY, Park SH, Park WH. Anti-cancer effects of auranofin in human lung cancer cells by increasing intracellular ROS levels and depleting GSH levels. Molecules. 2022;27:5207.
  7. Dadsena S, King LE, Garcia-Saez AJ. Apoptosis regulation at the mitochondria membrane level. Biochim Biophys Acta Biomembr. 2021;1863:183716.
  8. El Dika I, Makki I, Abou-Alfa GK. Hepatocellular carcinoma, novel therapies on the horizon. Chin Clin Oncol. 2021;10:12.
  9. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35:495-516. https://doi.org/10.1080/01926230701320337
  10. Fisusi FA, Akala EO. Drug combinations in breast cancer therapy. Pharm Nanotechnol. 2019;7:3-23. https://doi.org/10.2174/2211738507666190122111224
  11. Foerster F, Gairing SJ, Muller L, Galle PR. NAFLD-driven HCC: safety and efficacy of current and emerging treatment options. J Hepatol. 2022;76:446-57. https://doi.org/10.1016/j.jhep.2021.09.007
  12. Gao L, Loveless J, Shay C, Teng Y. Targeting ROS-mediated crosstalk between autophagy and apoptosis in cancer. Adv Exp Med Biol. 2020;1260:1-12. https://doi.org/10.1007/978-3-030-42667-5_1
  13. Garcia-Jimenez P, Just PM, Delgado AM, Robaina RR. Transglutaminase activity decrease during acclimation to hyposaline conditions in marine seaweed Grateloupia doryphora (Rhodophyta, Halymeniaceae). J Plant Physiol. 2007;164:367-70. https://doi.org/10.1016/j.jplph.2006.05.018
  14. Han Y, Chen P, Zhang Y, Lu W, Ding W, Luo Y, et al. Synergy between auranofin and celecoxib against colon cancer in vitro and in vivo through a novel redox-mediated mechanism. Cancers. 2019;11:931.
  15. Hwang-Bo H, Jeong JW, Han MH, Park C, Hong SH, Kim GY, et al. Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species. Gen Physiol Biophys. 2017;36:117-28. https://doi.org/10.4149/gpb_2016043
  16. Igarashi K, Kashiwagi K. The functional role of polyamines in eukaryotic cells. Int J Biochem Cell Biol. 2019;107:104-15. https://doi.org/10.1016/j.biocel.2018.12.012
  17. Kumar M, Reddy CRK, Ralph PJ. Polyamines in morphogenesis and development: a promising research area in seaweeds. Front Plant Sci. 2015;6:27.
  18. Li X, Zhou X, Liu X, Li X, Jiang X, Shi B, et al. Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway. Mol Med. 2022;28:103.
  19. Luo X, Kraus WL. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 2012;26:417-32. https://doi.org/10.1101/gad.183509.111
  20. Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018;359:eaan2788.
  21. Massai L, Cirri D, Marzo T, Messori L. Auranofin and its analogs as prospective agents for the treatment of colorectal cancer. Cancer Drug Resist. 2022;5:1-14. https://doi.org/10.20517/cdr.2021.71
  22. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73:4-13. https://doi.org/10.1002/hep.31288
  23. Moloney JN, Cotter TG. ROS signalling in the biology of cancer. Semin Cell Dev Biol. 2018;80:50-64. https://doi.org/10.1016/j.semcdb.2017.05.023
  24. Pegg AE. The function of spermine. IUBMB Life. 2014;66:8-18. https://doi.org/10.1002/iub.1237
  25. Plana D, Palmer AC, Sorger PK. Independent drug action in combination therapy: implications for precision oncology. Cancer Discov. 2022;12:606-24. https://doi.org/10.1158/2159-8290.CD-21-0212
  26. Prasad S, Gupta SC, Tyagi AK. Reactive oxygen species (ROS) and cancer: role of antioxidative nutraceuticals. Cancer Lett. 2017;387:95-105. https://doi.org/10.1016/j.canlet.2016.03.042
  27. Puleston DJ, Buck MD, Klein Geltink RI, Kyle RL, Caputa G, O'Sullivan D, et al. Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab. 2019;30:352-63. https://doi.org/10.1016/j.cmet.2019.05.003
  28. Rinaldi L, Vetrano E, Rinaldi B, Galiero R, Caturano A, Salvatore T, et al. HCC and molecular targeting therapies: back to the future. Biomedicines. 2021;9:1345.
  29. Roder C, Thomson MJ. Auranofin: repurposing an old drug for a golden new age. Drugs R D. 2015;15:13-20. https://doi.org/10.1007/s40268-015-0083-y
  30. Sun EJ, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Targeting the PI3K/Akt/mTOR pathway in hepatocellular carcinoma. Biomedicines. 2021;9:1639.
  31. Wakabayashi T, Ouhmich F, Gonzalez-Cabrera C, Felli E, Saviano A, Agnus V, et al. Radiomics in hepatocellular carcinoma: a quantitative review. Hepatol Int. 2019;13:546-59. https://doi.org/10.1007/s12072-019-09973-0
  32. Wang J, Li S, Wang J, Wu F, Chen Y, Zhang H, et al. Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function. Aging. 2020;12:650-71. https://doi.org/10.18632/aging.102647
  33. Warren CFA, Wong-Brown MW, Bowden NA. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis. 2019;10:177.
  34. Wen C, Wang H, Wu X, He L, Zhou Q, Wang F, et al. ROS-mediated inactivation of the PI3K/AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin. Cell Death Dis. 2019;10:809.
  35. Xu TT, Li H, Dai Z, Lau GK, Li BY, Zhu WL, et al. Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice. Aging. 2020;12:6401-14. https://doi.org/10.18632/aging.103035
  36. Ye DJ, Kwon YJ, Baek HS, Cho E, Kwon TU, Chun YJ. Combination treatment with auranofin and nutlin-3a induces synergistic cytotoxicity in breast cancer cells. J Toxicol Environ Health A. 2019;82:626-37.
  37. Yue F, Li W, Zou J, Jiang X, Xu G, Huang H, et al. Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. 2017;77:2938-51. https://doi.org/10.1158/0008-5472.CAN-16-3462
  38. Zhu J, Xiong Y, Zhang Y, Wen J, Cai N, Cheng K, et al. The molecular mechanisms of regulating oxidative stress-induced ferroptosis and therapeutic strategy in tumors. Oxid Med Cell Longev. 2020;2020:8810785.