Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion

Our plain-English summary of Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion, by B.R. You, W.H. Park (Oncology Reports, 2016).

The study

• Authors: B.R. You, W.H. Park
• Journal: Oncology Reports
• Published: 2016;35(1):546-51
• Cited by: 43 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Mesothelioma is an aggressive tumor associated with asbestos exposure. Auranofin as an inhibitor of thioredoxin reductase (TrxR) affects many biological processes such as inflammation and proliferation. In the present study, we investigated the cellular effects of auranofin on patient-derived mesothelioma cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. Basal TrxR1 levels have no difference between mesothelial cells and certain mesothelioma cells. In particular, ADA, CON and Hmeso mesothelioma cells showed lower levels of TrxR1 expression. Auranofin inhibited the proliferation of mesothelioma cells in a dose-dependent manner. Among mesothelioma cells were ADA and CON cells sensitive to auranofin. This agent also induced caspase-independent apoptosis and necrosis in ADA cells. In addition, auranofin increased ROS levels including O2(•-) and induced GSH depletion in mesothelioma cells. While N-acetyl cysteine (NAC) prevented cell death and decreased ROS levels in auranofin-treated mesothelioma cells, L-buthionine sulfoximine (BSO) intensified apoptosis and GSH depletion in these cells. In conclusion, auranofin induced mesothelioma cell death through oxidative stress and the death was regulated by the status of GSH content.

In plain English

This laboratory study used cells grown in dishes, not people, and did not study asbestos exposure. The authors compared baseline TrxR1 protein levels in two normal human mesothelial cell lines and seven patient-derived mesothelioma cell lines from Honolulu. They then tested auranofin, a rheumatoid arthritis drug that blocks TrxR, on mesothelioma cells. Treatments lasted 24 hours, and many experiments used 3 μM auranofin. TrxR1 levels did not differ between mesothelial and mesothelioma cells, but were lower in the ADA, CON and Hmeso mesothelioma lines. Auranofin reduced mesothelioma cell growth dose-dependently, and ADA and CON cells were more sensitive than other lines. In ADA cells, a caspase inhibitor did not change cell death markers, but a necrosis inhibitor and a necroptosis inhibitor reduced them. In the ADA and Phi lines, auranofin raised reactive oxygen species and depleted glutathione (GSH), a protective antioxidant. The antioxidant NAC prevented this cell death, while BSO, which blocks GSH production, increased apoptotic death. The authors concluded that auranofin killed mesothelioma cells through oxidative stress, affected by GSH content. The supplied text gives no numerical values for the measured outcomes, which appear only in figures not included.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell culture experiment
• Who was studied: Two human mesothelial cell lines (HM69 and HM72) and seven patient-derived human mesothelioma cell lines (ADA, CON, Hmeso, Mill, Phi, REN and ROB), obtained from Queen's Medical Center, Honolulu, USA. All nine lines were compared for baseline TrxR1 protein levels. Auranofin treatment results are reported for mesothelioma cells, and most follow-up experiments used the ADA and Phi lines.
• Exposure: The drug auranofin (a TrxR inhibitor), often at 3 μM for 24 hours. Some cells were first pretreated for 1 hour with NAC (2 mM), BSO (10 μM), the caspase inhibitor Z-VAD (15 μM), NecroX-2 (1 μM) or necrostatin-1 (50 μM). Asbestos exposure was not studied.
• Main results:
  • Basal TrxR1 protein levels did not differ between mesothelial and mesothelioma cells. Among the mesothelioma lines, ADA, CON and Hmeso had lower TrxR1 levels than the others.
  • Auranofin reduced the proliferation of mesothelioma cells in a dose-dependent manner.
  • ADA and CON cells, which had low TrxR1 levels, were more sensitive to auranofin than other mesothelioma cells.
  • Auranofin increased markers of cell death in ADA and Phi cells. LDH release (a necrosis marker) was high in Phi cells, while sub-G1 and Annexin V positive cells were high in ADA cells.
  • In auranofin-treated ADA cells, the caspase inhibitor Z-VAD did not change the percentages of sub-G1 and Annexin V positive cells. A necrosis inhibitor (NecroX) and a necroptosis inhibitor (necrostatin-1) both reduced these numbers.
  • Auranofin increased reactive oxygen species levels, including superoxide, in ADA and Phi cells, and increased GSH depletion in both lines.
  • NAC significantly prevented cell death in auranofin-treated ADA and Phi cells, most strongly in ADA cells. It also completely blocked auranofin-induced GSH depletion.
  • BSO significantly increased apoptotic cell death in auranofin-treated ADA and Phi cells.
• The authors' conclusion: The authors concluded that, in what they call the first report of this kind, auranofin inhibited proliferation of mesothelioma cells and induced their death through oxidative stress. They also concluded that this death was affected by the cells' GSH content.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Oxidative Stress, Asbestos Exposure, Inflammation, Reactive Oxygen Species (ROS), Glutathione (GSH), Mesothelial Cells, Apoptosis.

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