Taurolidine and oxidative stress: a rationale for local treatment of mesothelioma

Our plain-English summary of Taurolidine and oxidative stress: a rationale for local treatment of mesothelioma, by N. Aceto, P. Bertino, D. Barbone, et al (The European Respiratory Journal, 2009).

The study

• Authors: N. Aceto, P. Bertino, D. Barbone, G. Tassi, L. Manzo, C. Porta, L. Mutti, G. Gaudino
• Journal: The European Respiratory Journal
• Published: 2009;34(6):1399-407
• Cited by: 20 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is an asbestos-related, aggressive tumour, resistant to most anticancer therapies. Akt is a key mediator of mesothelioma cell survival and chemoresistance. This study aimed to clarify the mechanism by which taurolidine (TN), a known synthetic compound with antimicrobial and antineoplastic properties, leads to mesothelioma cell death. Apoptosis was studied by annexin V binding, cell cycle analysis, caspase-8 activation, poly(ADP-ribose) polymerase (PARP) cleavage and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling (TUNEL). Oxidative stress was measured by nitrite production and DNA oxidative damage. Protein expression and phosphorylation were evaluated by immunoprecipitation and immunoblotting. TN induces cell death of mesothelioma cells, but not of non-neoplastic human mesothelial cells. After TN treatment of mesothelioma cells, Akt but not extracellular signal-regulated kinase (Erk) 1/2 activity is inhibited a in time- and dose-dependent manner. Protein phosphatase (PP)1alpha and PP2A are activated several hours after drug addition. Apoptosis induced by TN is driven by oxidative stress and cell exposure to sulfydryl donors, such as glutathione monoethylester and l-N-acetylcysteine, significantly reduced pro-apoptotic effects and Akt inhibition. Conversely, expression of constitutively activated Akt did not affect cytoxicity elicited by TN, which retained its ability to inhibit the kinase. TN induces mesothelioma cell death via oxidative stress, accompanied by inhibition of Akt signalling. This provides a promising molecular rationale for TN as local treatment of malignant mesothelioma.

In plain English

This was a laboratory study of cells grown in dishes. No patients or animals were treated, and asbestos exposure itself was not studied. The authors tested taurolidine, an antibacterial drug, on two human malignant mesothelioma cell lines (MMB and MMP, taken from pleural effusions of patients) and on two non-cancerous human mesothelial cell lines. Skin fibroblasts and lung carcinoma cells served as comparisons. In a cell viability test, taurolidine had a significant toxic effect on the mesothelioma cells, and the lung carcinoma cells also showed a toxic response, while non-cancerous cells showed negligible toxicity. In the mesothelioma cells it triggered programmed cell death (apoptosis), reduced the activity of a survival protein called Akt, and increased signs of oxidative stress (nitrite production and oxidative DNA damage). In MMP cells, apoptotic nuclei rose from 3.1% in untreated cells to 14.1% with taurolidine. Adding the antioxidants glutathione monoethylester or N-acetylcysteine lowered this to 2.6% and 3.1%, respectively. The authors concluded that taurolidine kills mesothelioma cells through oxidative stress, together with Akt inhibition, and that this provides a rationale for taurolidine as a local treatment for malignant mesothelioma.

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) experiment on human cell lines grown in culture
• Who was studied: Cell lines, not people: two human malignant mesothelioma cell lines (MMB and MMP) derived from pleural effusions of malignant mesothelioma patients; two non-neoplastic human mesothelial cell lines (primary HMCs from patients with congestive heart failure, and MET5A); and, as controls, human dermal fibroblasts and A549 human lung carcinoma cells
• Exposure: The drug taurolidine, an antibacterial agent, at a range of concentrations and treatment times. No asbestos exposure was studied. Some cells were also given the antioxidants glutathione monoethylester or N-acetylcysteine.
• Main results:
  • In the viability (MTT) assay, taurolidine had a significant cytotoxic effect on MMB, MMP and A549 cancer cells compared with non-neoplastic cells. Non-neoplastic cells, mesothelial or not, showed negligible cytotoxicity.
  • Taurolidine caused apoptosis in mesothelioma cells. Apoptosis was far higher in MMB cells than in MMP cells.
  • Taurolidine inhibited Akt and p70S6K phosphorylation only in the mesothelioma cells (MMP and MMB), not in non-neoplastic HMCs.
  • Nitrite production, a marker of oxidative stress, occurred early and only in mesothelioma cells.
  • The increase in oxidative DNA damage (8-OHdG adducts) after taurolidine was significantly higher in mesothelioma cells than in non-neoplastic mesothelial cells.
  • In MMP mesothelioma cells, 14.1% of nuclei were apoptotic after taurolidine for 24 h, compared with 3.1% in untreated cells.
  • In MMP cells, adding glutathione monoethylester or N-acetylcysteine to taurolidine lowered apoptotic nuclei to 2.6% and 3.1%, respectively. The authors reported these differences as statistically significant.
  • In MMP cells, pre-treatment with glutathione monoethylester completely prevented the Akt inhibition caused by taurolidine.
  • MMB cells made to express a permanently active form of Akt showed no difference from ordinary MMB cells in cell viability after taurolidine. These data were not shown in the article.
• The authors' conclusion: The authors concluded that taurolidine selectively induces mesothelioma cell death via oxidative stress and by reducing Akt activity, and that their study provides a rationale for taurolidine as a novel local treatment for malignant mesothelioma.
• Limitations the authors state:
  • The authors stated that the mechanism by which taurolidine affects Akt was not identified.

Topics

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

Medical terms in this study, explained in our Lexicon: Oxidative Stress, Mesothelioma, Malignant Mesothelioma, Apoptosis, Mesothelial Cells, Glutathione (GSH).

Related studies

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• Phagocytosis of crocidolite asbestos induces oxidative stress, DNA damage, and apoptosis in mesothelial cells — W. Liu, J.D. Ernst, et al. (2000)
• Oxidative stress-mediated cytotoxicity and apoptosis induction by TiO2 nanofibers in HeLa cells — K.M. Ramkumar, C. Manjula, et al. (2012)
• Auranofin induces mesothelioma cell death through oxidative stress and GSH depletion — B.R. You, W.H. Park (2016)
• Dispersion medium modulates oxidative stress response of human lung epithelial cells upon exposure to carbon nanomaterial samples — E. Herzog, H.J. Byrne, et al. (2009)
• Raw single-wall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells — M. Pacurari, X.J. Yin, et al. (2008)

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