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

N. Aceto, P. Bertino, D. Barbone, G. Tassi, L. Manzo, C. Porta, L. Mutti, G. Gaudino

Research output: Contribution to journalArticle

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 transferasemediated 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)1a 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. Copyright

Original languageEnglish
Pages (from-to)1399-1407
Number of pages9
JournalEuropean Respiratory Journal
Volume34
Issue number6
DOIs
Publication statusPublished - Dec 2009

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Keywords

  • Akt
  • Apoptosis
  • Malignant mesothelioma
  • Oxidative stress
  • Taurolidine

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Aceto, N., Bertino, P., Barbone, D., Tassi, G., Manzo, L., Porta, C., Mutti, L., & Gaudino, G. (2009). Taurolidine and oxidative stress: A rationale for local treatment of mesothelioma. European Respiratory Journal, 34(6), 1399-1407. https://doi.org/10.1183/09031936.00102308