Anti-Cancer Effects of Auranofin in Human Lung Cancer Cells by Increasing Intracellular ROS Levels and Depleting GSH Levels

Cui, Xia-Ying; Park, Sun-Hyang; Park, Woo-Hyun

doi:10.3390/molecules27165207

Cited by 24 publications

(32 citation statements)

References 73 publications

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“…Myosin (MYH-9), plectin (PLEC), talin (TLN1), and annexins are responsible for cell–cell and cell–protein interactions accompanied by kinase M3K5 make up the system responsible for cytoskeleton reorganization essential for the cell motility and the wound healing process [ 20 , 55 ]. The abundance of peptides representing those proteins significantly decreased due to the exposure of cells to auranofin.…”

Section: Resultsmentioning

confidence: 99%

“…Both moieties of auranofin can inhibit thioredoxin reductase (TrxR) and glutathione peroxidase (GPx) [ 18 , 19 ]. As both proteins contain thiol and selenol groups, auranofin’s presence also significantly depletes the reduced form of glutathione [ 20 ]. All three biocompounds are responsible for ROS regulation, and their amounts tend to be significantly higher in cancer cells, especially in non-small cell lung carcinoma [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Speciation Analysis Highlights the Interactions of Auranofin with the Cytoskeleton Proteins of Lung Cancer Cells

et al. 2022

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Two types of lung cells (epithelial cancer lung cells, A-549 and lung fibroblasts MRC-5) were exposed to the clinically established gold drug auranofin at concentrations close to the half-maximal inhibitory drug concentrations (IC50). Collected cells were subjected to speciation analysis using inductively coupled plasma mass spectrometry (ICP-MS). Auranofin showed better affinity toward proteins than DNA, RNA, and hydrophilic small molecular weight compounds. It can bind to proteins that vary in size (~20 kDa, ~75 kDa, and ≥200 kDa) and pI. However, the possibility of dimerization and protein–protein complex formation should also be taken into account. µRPLC/CZE-ESI-MS/MS studies on trypsinized proteins allowed the indication of 76 peptides for which signal intensity was influenced by auranofin presence in cells. Based on it, identity was proposed for 20 proteins. Except for thioredoxin reductase (TrxR), which is directly targeted by gold complex, the proteins were found to be transformed. Five indicated proteins: myosin, plectin, talin, two annexins, and kinase M3K5, are responsible for cell–cell, cell–protein interactions, and cell motility. A wound healing test confirmed their regulation by auranofin as cell migration decreased by 40% while the cell cycle was not interrupted.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Speciation Analysis Highlights the Interactions of Auranofin with the Cytoskeleton Proteins of Lung Cancer Cells

et al. 2022

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“…For example, the nitrated [6,6,6]tricycle-derived compound SK1 triggered GSH depletion, leading to ROS overproduction in oral cancer cells [ 49 ]. Auranofin exhibits antiproliferation by ROS induction and GSH depletion in lung cancer cells [ 50 ]. Moreover, examining the status of antioxidant levels for 3HDT treatment is necessary because oxidative stress was upregulated.…”

Section: Discussionmentioning

confidence: 99%

Ginger-Derived 3HDT Exerts Antiproliferative Effects on Breast Cancer Cells by Apoptosis and DNA Damage

Chen

Shiau

et al. 2023

IJMS

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Ginger-derived compounds are abundant sources of anticancer natural products. However, the anticancer effects of (E)-3-hydroxy-1-(4′-hydroxy-3′,5′-dimethoxyphenyl)-tetradecan-6-en-5-one (3HDT) have not been examined. This study aims to assess the antiproliferation ability of 3HDT on triple-negative breast cancer (TNBC) cells. 3HDT showed dose-responsive antiproliferation for TNBC cells (HCC1937 and Hs578T). Moreover, 3HDT exerted higher antiproliferation and apoptosis on TNBC cells than on normal cells (H184B5F5/M10). By examining reactive oxygen species, mitochondrial membrane potential, and glutathione, we found that 3HDT provided higher inductions for oxidative stress in TNBC cells compared with normal cells. Antiproliferation, oxidative stress, antioxidant signaling, and apoptosis were recovered by N-acetylcysteine, indicating that 3HDT preferentially induced oxidative-stress-mediated antiproliferation in TNBC cells but not in normal cells. Moreover, by examining γH2A histone family member X (γH2AX) and 8-hydroxy-2-deoxyguanosine, we found that 3HDT provided higher inductions for DNA damage, which was also reverted by N-acetylcysteine. In conclusion, 3HDT is an effective anticancer drug with preferential antiproliferation, oxidative stress, apoptosis, and DNA damage effects on TNBC cells.

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“…Cancer treatment targeting the developed antioxidant system in cancer cells is a promising and efficient approach ( Moloney & Cotter, 2018;Prasad et al, 2017). Auranofin exerts anticancer activity by inducing oxidative stress, which increases ROS generation through TrxR inhibition (Cui et al, 2022;Hwang-Bo et al, 2017). Spermidine, selected as the second drug in the combination therapy, is a polyamine abundant in seaweed and exerts various biological functions (Kumar et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Auranofin is a thioredoxin reductase (TrxR) inhibitor, which acts as a regulator of cellular redox, cell proliferation, and a component of antioxidant systems (Abdalbari & Telleria, 2021). Cui et al (2022) have demonstrated that auranofin can induce apoptosis in human lung cancer cells by increasing the accumulation of reactive oxygen species (ROS) via inhibition of TrxR activity and glutathione depletion. Furthermore, auranofin exerts anticancer activity by inactivating extracellular signal-regulating kinase and protein kinase B (Akt), accompanied by mitochondrial dysfunction through the modulation of B-cell lymphoma 2 (Bcl-2) family proteins (Wen et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Auranofin accelerates spermidine-induced apoptosis via reactive oxygen species generation and suppression of PI3K/Akt signaling pathway in hepatocellular carcinoma

Hwangbo¹,

Kim²,

Kim³

et al. 2023

Fish Aquat Sci

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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 (IC 50 ) 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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Anti-Cancer Effects of Auranofin in Human Lung Cancer Cells by Increasing Intracellular ROS Levels and Depleting GSH Levels

Cited by 24 publications

References 73 publications

Speciation Analysis Highlights the Interactions of Auranofin with the Cytoskeleton Proteins of Lung Cancer Cells

Speciation Analysis Highlights the Interactions of Auranofin with the Cytoskeleton Proteins of Lung Cancer Cells

Ginger-Derived 3HDT Exerts Antiproliferative Effects on Breast Cancer Cells by Apoptosis and DNA Damage

Auranofin accelerates spermidine-induced apoptosis via reactive oxygen species generation and suppression of PI3K/Akt signaling pathway in hepatocellular carcinoma

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