Auranofin accelerates spermidine-induced apoptosis via reactive oxygen species generation and suppression of PI3K/Akt signaling pathway in hepatocellular carcinoma
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
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.
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.
참고문헌 (38)
- Abdalbari FH, "The gold complex auranofin : new perspectives for cancer therapy", Discov Oncol, 12, pp.42~ (2021)
- Chakraborty E, "Emerging therapies for hepatocellular carcinoma(HCC)", Cancers, 14, pp.2798~ (2022)
- Chen S, "Targeted therapy for hepatocellular carcinoma : challenges and opportunities", Cancer Lett, 460, pp.1~9 (2019)
- Cohen GM, "Caspases : the executioners of apoptosis", Biochem J, 326, pp.1~16 (1997)
- Cucarull B, "Hepatocellular carcinoma : molecular pathogenesis and therapeutic advances", Cancers, 14, pp.621~ (2022)
- Cui XY, "Anti-cancer effects of auranofin in human lung cancer cells by increasing intracellular ROS levels and depleting GSH levels", Molecules, 27, pp.5207~ (2022)
- Dadsena S, "Apoptosis regulation at the mitochondria membrane level", Biochim Biophys Acta Biomembr, 1863, pp.183716~ (2021)
- El Dika I, "Hepatocellular carcinoma, novel therapies on the horizon", Chin Clin Oncol, 10, pp.12~ (2021)
- Elmore S, "Apoptosis : a review of programmed cell death", Toxicol Pathol, 35, pp.495~516 (2007)
- Fisusi FA, "Drug combinations in breast cancer therapy", Pharm Nanotechnol, 7, pp.3~23 (2019)
- Foerster F, "NAFLD-driven HCC : safety and efficacy of current and emerging treatment options", J Hepatol, 76, pp.446~457 (2022)
- Gao L, "Targeting ROS-mediated crosstalk between autophagy and apoptosis in cancer", Adv Exp Med Biol, 1260, pp.1~12 (2020)
- García-Jiménez P, "Transglutaminase activity decrease during acclimation to hyposaline conditions in marine seaweed Grateloupia doryphora(Rhodophyta, Halymeniaceae)", J Plant Physiol, 164, pp.367~370 (2007)
- Han Y, "Synergy between auranofin and celecoxib against colon cancer in vitro and in vivo through a novel redox-mediated mechanism", Cancers, 11, pp.931~ (2019)
- Hwang-Bo H, "Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species", Gen Physiol Biophys, 36, pp.117~128 (2017)
- Igarashi K, "The functional role of polyamines in eukaryotic cells", Int J Biochem Cell Biol, 107, pp.104~115 (2019)
- Kumar M, "Polyamines in morphogenesis and development: a promising research area in seaweeds", Front Plant Sci, 6, pp.27~ (2015)
- Li X, "Spermidine protects against acute kidney injury by modulating macrophage NLRP3 inflammasome activation and mitochondrial respiration in an eIF5A hypusination-related pathway", Mol Med, 28, pp.103~ (2022)
- Luo X, "On PAR with PARP : cellular stress signaling through poly(ADP-ribose)and PARP-1", Genes Dev, 26, pp.417~432 (2012)
- Madeo F, "Spermidine in health and disease", Science, 359, pp.eaan2788~ (2018)
- Massai L, "Auranofin and its analogs as prospective agents for the treatment of colorectal cancer", Cancer Drug Resist, 5, pp.1~14 (2022)
- McGlynn KA, "Epidemiology of hepatocellular carcinoma", Hepatology, 73, pp.4~13 (2021)
- Moloney JN, "ROS signalling in the biology of cancer", Semin Cell Dev Biol, 80, pp.50~64 (2018)
- Pegg AE, "The function of spermine", IUBMB Life, 66, pp.8~18 (2014)
- Plana D, "Independent drug action in combination therapy : implications for precision oncology", Cancer Discov, 12, pp.606~624 (2022)
- Prasad S, "Reactive oxygen species(ROS)and cancer : role of antioxidative nutraceuticals", Cancer Lett, 387, pp.95~105 (2017)
- Puleston DJ, "Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation", Cell Metab, 30, pp.352~363 (2019)
- Rinaldi L, "HCC and molecular targeting therapies : back to the future", Biomedicines, 9, pp.1345~ (2021)
- Roder C, "Auranofin : repurposing an old drug for a golden new age", Drugs R D, 15, pp.13~20 (2015)
- Sun EJ, "Targeting the PI3K", Akt, Biomedicines, pp.2021, 9[DOI]
- Wakabayashi T, "Radiomics in hepatocellular carcinoma : a quantitative review", Hepatol Int, 13, pp.546~559 (2019)
- Wang J, "Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function", Aging, 12, pp.650~671 (2020)
- Warren CFA, "BCL-2 family isoforms in apoptosis and cancer", Cell Death Dis, 10, pp.177~ (2019)
- Wen C, "ROS-mediated inactivation of the PI3K", AKT pathway is involved in the antigastric cancer effects of thioredoxin reductase-1 inhibitor chaetocin, 2019, pp.10, 809~
- Xu TT, "Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice", Aging, 12, pp.6401~6414 (2020)
- Ye DJ, "Combination treatment with auranofin and nutlin-3a induces synergistic cytotoxicity in breast cancer cells", J Toxicol Environ Health A, 82, pp.626~637 (2019)
- Yue F, "Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy", Cancer Res, 77, pp.2938~2951 (2017)
- Zhu J, "The molecular mechanisms of regulating oxidative stress-induced ferroptosis and therapeutic strategy in tumors", Oxid Med Cell Longev, 2020, pp.8810785~ (2020)